Recommendations on practice of conditioned pain modulation (CPM) testing

Protocols for testing conditioned pain modulation (CPM) vary between different labs/clinics. In order to promote research and clinical application of this tool, we summarize the recommendations of interested researchers consensus meeting regarding the practice of CPM and report of its results.     

A two-year prospective controlled study of bone mass and bone turnover in children with early juvenile idiopathic arthritis

OBJECTIVE: To explore early changes and predictors of bone mass in children with juvenile idiopathic arthritis (JIA) in order to identify patients who will develop bone mass reductions. METHODS: We conducted a prospective cohort study of 108 children with early JIA (ages 6-18 years; mean disease duration 19.3 months) who were individually matched with 108 healthy children for age, sex, race, and county of residence. Bone mass and changes in total body, spine, femur, and forearm bone mineral density and bone mineral content (BMC), body composition, growth, and biochemical parameters of bone turnover were examined at baseline and at followup a mean of 24 months later. Low bone mass was defined as a Z score >1 SD below the reference population. RESULTS: Of the 200 children evaluated at followup, the 100 healthy children had greater gains in total body BMC (P = 0.035), distal radius BMC (P < 0.001), and total body lean mass (P < 0.001) than did the 100 JIA patients. Low or very low total body BMC was observed in 24% of the patients and 12% of the healthy children. Bone formation, bone resorption, and weight-bearing activities were reduced in the patients compared with the healthy children. Multiple regression analysis showed that in patients with JIA, serum bone-specific alkaline phosphatase, serum C-telopeptide of type I collagen, and weight-bearing activities were independent predictors of changes in total body BMC. Total body BMC was lower in patients with polyarticular onset than in those with oligoarticular disease onset. CONCLUSION: Patients with JIA have moderate reductions in bone mass gains, bone turnover, and total body lean mass early in the disease course.     

Superior protection conferred by inactivated whole virus vaccine over subunit and DNA vaccines against salmonid alphavirus infection in Atlantic salmon (Salmo salar L.)

Salmonid alphavirus 3 (SAV-3) is an emerging pathogen in Norwegian salmon farming and causes severe annual losses. We studied the immunogenicity and protective ability of subunit and DNA vaccines based on E1 and E2 spike proteins of salmonid alphavirus subtype 3 (SAV-3), and compared these to an experimental inactivated, whole virus (IWV) vaccine in Atlantic salmon. The antigens were delivered as water-in-oil emulsions for the subunit and inactivated vaccines and non-formulated for the DNA vaccines. The IWV and the E2 subunit prime-boost groups had circulating neutralizing antibodies at challenge, correlating with high protection against lethal challenge and 3-log(10) reduction of virus titer in heart for the IWV group. Prime-boost with E1 subunit vaccine also conferred significant protection against mortality, but did not correlate with neutralizing antibody levels. Protection against pathology in internal organs was only seen for the IWV group. Prime-boost with E1 and E2 DNA vaccines showed marginal protection in terms of reduction of viral replication in target organs and protection against mortality was not different from controls. The IWV group showed significant upregulation of IFNγ and IL2 mRNA expression at 4 weeks post challenge possibly indicating that other mechanisms in addition to antibody responses play a role in mediating protection against infection. This is the first report comparing the immunogenicity and protection against mortality for IWV vaccines and spike protein subunit and DNA vaccines against salmonid alphavirus infection in Atlantic salmon. The IWV vaccine has superior immunogenicity over sub-unit and DNA vaccines.     

Widespread Hyperalgesia in Adolescents With Symptoms of Irritable Bowel Syndrome: Results From a Large Population-Based Study

Widespread hyperalgesia is well documented among adult patients with irritable bowel syndrome (IBS), but little is known about pain sensitivity among adolescents with IBS. We examined pain sensitivity in 961 adolescents from the general population (mean age 16.1 years), including pain threshold and tolerance measurements of heat (forearm) and pressure pain (fingernail and shoulder) and cold pressor tolerance (hand). Adolescents with IBS symptoms (Rome III criteria) had lower heat pain thresholds compared to controls after adjustments for sex, comorbid pain, and psychological distress (mean difference = –.8°C; 95% confidence interval [CI] = ?1.6 to ?.04). Similar results were found for pressure pain threshold at the shoulder (mean difference = ?46 kPa; 95% CI = ?78 to ?13) and fingernail (mean difference = –62 kPa; 95% CI = ?109 to ?15), and for an aggregate of all 3 threshold measures (z-score difference = ?.4; 95% CI = ?.6 to ?.2), though pressure pain threshold differences were nonsignificant after the final adjustments for psychological distress. No difference of pain tolerance was found between the IBS cases and controls. Our results indicate that adolescents in the general population with IBS symptoms, like adults, have widespread hyperalgesia.PerspectiveThis is the first report of widespread hyperalgesia among adolescents with IBS symptoms in the general population, with lower pain thresholds found to be independent of sex and comorbid pain. Our results suggest that central pain sensitization mechanisms in IBS may contribute to triggering and maintaining chronic pain symptoms.     

RAMP2 and RAMP3 mRNA levels are increased in failing rat cardiomyocytes and associated with increased responsiveness to adrenomedullin

Adrenomedullin (AM) is a potent vasorelaxing peptide with natriuretic and diuretic actions. Recent data indicate that AM may function as an endogenous regulator of cardiac function. We investigated to what extent AM, the AM receptor subtypes, and AM receptor-associated proteins were regulated in cardiomyocytes and non-cardiomyocytes of rats with congestive heart failure (CHF), and whether such regulation was paralleled by corresponding alterations of functional responses to AM. Cardiomyocytes and non-cardiomyocytes were isolated from myocardial tissue of rats 7 days after induction of myocardial infarction or sham operation. AM immunoreactivity was found in cardiomyocytes, endothelial cells, and fibroblasts. Robust increase of AM mRNA levels was observed both in the cardiomyocytes and in the non-cardiomyocytes of CHF rats compared to that of sham-operated rats (2.7-fold and 3.7-fold, respectively, P <0.05). Fairly high mRNA levels and immunoreactivity against the AM receptor chaperone receptor activity-modifying protein-2 (RAMP2) were also detected in the cardiomyocytes and non-cardiomyocytes. However, induction of RAMP2 mRNA expression was restricted to cardiomyocytes (1.8-fold increase in cardiomyocytes from CHF rats vs. sham rats; P <0.05). In contrast, very low levels of RAMP3 mRNA were observed. RAMP3 mRNA levels, however, were elevated in both cardiomyocytes and non-cardiomyocytes from CHF rats (6.5-fold and 2.4-fold increase vs. sham rats, respectively; P <0.05). Parallel increases of specific AM receptor binding sites and of AM-stimulated adenylyl cyclase activities were observed in failing cardiomyocytes compared to cardiomyocytes from sham rats (fivefold and sixfold increase, respectively; P <0.05). Thus, this study demonstrates that AM mRNA levels, AM receptor binding sites, and AM-stimulated adenylyl cyclase activities are increased in cardiomyocytes from failing rat hearts. Furthermore, our data suggest that induction of RAMP2 and RAMP3 contributes to the increased responsiveness to AM in failing cardiomyocytes.     

Hepatic autotransplantation with ex situ neoplasm extirpation and vena cava replacement

The treatment of a 64-year-old man with a retrohepatic neoplasm deemed not accessible by conventional in situ surgical techniques is presented to illustrate the potential benefit offered by techniques adapted from liver transplantation and vascular surgery. A computed tomography scan performed for uncharacteristic abdominal discomfort revealed a hepatic or retrohepatic tumor compressing the inferior vena cava. Biopsies were interpreted as probably leiomyoma or malignant schwannoma. The liver with neoplasm and retrohepatic inferior vena cava was removed en bloc and taken to the back table where the neoplasm invading the inferior vena cava wall was removed together with the inferior vena cava. The inferior vena cava was then replaced by a 22-mm polytetrafluoroethylene graft and the 3 hepatic veins were reconstructed with anastomoses to this graft. The liver was then autotransplanted by standard transplantation technique. The postoperative course was uneventful and the patient is in good health more than 2 years after surgery.     

Rescue therapy with tacrolimus (FK 506) in renal transplant recipients —a Scandinavian multicenter analysis

All renal allograft recipients (n = 32) in Sweden and Norway who were converted from cyclosporin(CyA)-based immunosuppression to FK 506 (tacrolimus) between October 1992 and June 1995 were analyzed retrospectively. The reasons for conversion were acute refractory rejection (n = 21), chronic rejection (n = 4), and suspected CyA toxicity (n = 6); one patient was converted for psychological reasons. The mean time from transplantation to conversion was 29 (range 1–243) weeks and there was a mean follow-up of 46 (2–143) weeks. Overall graft survival was 59%, with graft survival 52% in patients converted because of acute rejection, 50% in patients converted because of chronic rejection, and 83% in patients converted because of CyA toxicity. There was no significant correlation between preconversion serum creatinine and outcome. Seventy-two percent of the patients had significant side effects during FK 506 treatment, the most frequent ones being neurological and gastrointestinal symptoms. These improved after dose reduction. Two patients became overimmunosuppressed and developed lymphoma. One patient died of the primary kidney disease, hemolytic uraemic syndrome. We conclude that FK 506 therapy is able to salvage kidneys with acute refractory rejection and that it is an alternative in patients with CyA toxicity. However, the risk of overimmunosuppression must be considered.     

cDNA microarray analysis of non-selected cases of acute myeloid leukemia demonstrates distinct clustering independent of cytogenetic aberrations and consistent with morphological signs of differentiation

Acute myeloid leukemia (AML) is a heterogeneous disease with respect to biology and clinical course. Until now the basis for prognostic evaluation and therapeutic decision has been the karyotype, genetic FLT3 abnormalities and the initial chemotherapy response. A question that has emerged is if extensive gene expression analysis may supplement or partly replace current diagnostics. In an attempt to address this question, we performed cDNA microarray analysis on peripheral blood samples of 25 patients with newly diagnosed AML with high blast counts. The patients were randomly selected from a large group of consecutive patients. Leave-one-out crossvalidation (LOOCV) showed with high accuracy that gene expression classifiers could predict if leukaemia samples belonged to the FAB AML-M1 or to the FAB AML-M2 groups. An unsupervised two-dimensional hierarchical cluster analysis generated 3 patient subgroups. Except for an accumulation of samples classified as FAB M1 and M2 in cluster 3, there was no evident relationship between the clusters and the FAB classification. Each subgroup displayed clearly distinguished gene expression patterns validated using real-time quantitative PCR analysis. The identification of specific gene expressions that together constitute regulatory modules must complement cluster analyses in order to achieve an accurate basis for prognosis and prediction.