Predicting the development of clinical arthritis in anti-CCP positive individuals with non-specific musculoskeletal symptoms: a prospective observational cohort study.

OBJECTIVES: To monitor progression to inflammatory arthritis (IA) in individuals with non-specific musculoskeletal (MSK) symptoms and positive anticyclic citrullinated peptide (anti-CCP) antibodies. To develop a pragmatic model to predict development of IA in this patient group. METHODS: In this prospective observational cohort, patients with new non-specific MSK symptoms and positive anti-CCP were recruited from regional primary care and secondary care referrals. Clinical, imaging and serological parameters were assessed at baseline. Cox regression analysis was performed to identify predictors of progression to IA and develop a risk score to stratify patients at presentation. FINDINGS: 100 consecutive patients (73 women, mean age 51 years) were followed up for median 19.8 months (range 0.1-69.0); 50 developed IA after a median 7.9 months (range 0.1-52.4), 34 within 12 months. The majority (43/50) fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for rheumatoid arthritis. A model for progression to IA was devised using four variables: tenderness of hand or foot joints, early morning stiffness ≥30 min, high-positive autoantibodies, and positive ultrasonographic power Doppler signal. None of the five individuals at low risk (score 0) progressed to IA, compared with 31% of 29 at moderate risk (1-2) and 62% of 66 at high risk (≥3). Adding shared epitope increased the number at low risk (score 0-1; 0/11 progressed). CONCLUSIONS: In patients presenting with non-specific MSK symptoms and anti-CCP, the risk of progression to IA could be quantified using data available in clinical practice. The proposed risk score may be used to stratify patients for early therapeutic intervention. TRIAL REGISTRATION NUMBER: NCT02012764 at ClinicalTrials.gov.

A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial.

OBJECTIVE: To compare the efficacy of etanercept (ETN) and methotrexate (MTX) versus MTX monotherapy for remission induction in patients with early inflammatory arthritis. METHODS: In a 78-week multicentre randomised placebo-controlled superiority trial, 110 DMARD-naïve patients with early clinical synovitis (≥1 tender and swollen joint, and within 3 months of diagnosis) and either rheumatoid factor, anticitrullinated protein antibodies or shared epitope positive were randomised 1:1 to receive MTX+ETN or MTX+placebo (PBO) for 52 weeks. Injections (ETN or PBO) were stopped in all patients at week 52. In those with no tender or swollen joints (NTSJ) for >26 weeks, injections were stopped early. If patients had NTSJ >12 weeks after stopping the injections, MTX was weaned. The primary endpoint was NTSJ at week 52. RESULTS: No statistically significant difference was seen for the primary endpoint (NTSJ at week 52 (32.5% vs 28.1% [adjusted OR 1.32 (0.56 to 3.09), p=0.522]) in the MTX+ETN and MTX+PBO groups, respectively). The secondary endpoints did not differ between groups at week 52 or 78. Exploratory analyses showed a higher proportions of patients with DAS28-CRP<2.6 in the MTX+ETN group at week 2 (38.5% vs 9.2%, adjusted OR 8.87 (2.53 to 31.17), p=0.001) and week 12 (65.1% vs 43.8%, adjusted OR 2.49 (1.12 to 5.54), p=0.026). CONCLUSIONS: In this group of patients with early inflammatory arthritis, almost a third had no tender, swollen joints after 1 year. MTX+ETN was not superior to MTX monotherapy in achieving this outcome. Clinical responses, however, including DAS28-CRP<2.6, were achieved earlier with MTX+ETN combination therapy. TRIAL REGISTRATION NUMBER: The EMPIRE trial is registered on the following trial registries: Eudract-2005-005467-29; ISRCTN 55428162 (http://www.controlled-trials.com/ISRCTN55428162/EMPIRE). The full trial protocol can be obtained from the corresponding author.

Remission induction comparing infliximab and high-dose intravenous steroid, followed by treat-to-target: a double-blind, randomised, controlled trial in new-onset, treatment-naive, rheumatoid arthritis (the IDEA study).

OBJECTIVES: In disease modifying antirheumatic drug (DMARD)-naive early rheumatoid arthritis (RA), to compare the efficacy of methotrexate (MTX) and infliximab (IFX) with MTX and intravenous corticosteroid for remission induction. METHODS: In a 78-week multicentre randomised controlled trial, double-blinded to week 26, 112 treatment-naive RA patients (1987 American College of Rheumatology classification criteria) with disease activity score 44 (DAS44)>2.4 were randomised to MTX + IFX or MTX + single dose intravenous methylprednisolone 250 mg. A treat-to-target approach was used with treatment escalation if DAS44>2.4. In the IFX group, IFX was discontinued for sustained remission (DAS44<1.6 for 6 months). The primary outcome was change in modified total Sharp-van der Heijde score (mTSS) at week 50. RESULTS: The mean changes in mTSS score at week 50 in the IFX and intravenous steroid groups were 1.20 units and 2.81 units, respectively (adjusted difference (95% CI) -1.45 (-3.35 to 0.45); p=0.132). Radiographic non-progression (mTSS<2.0) occurred in 81% vs 71% (OR 1.77 (0.56 to 5.61); p=0.328). DAS44 remission was achieved at week 50 in 49% and 36% (OR 2.13 (0.91 to 5.00); p=0.082), and at week 78 in 48% and 50% (OR 1.12 (0.47 to 2.68); p=0.792). Exploratory analyses suggested higher DAS28 remission at week 6 and less ultrasound synovitis at week 50 in the IFX group. Of the IFX group, 25% (14/55) achieved sustained remission and stopped IFX. No substantive differences in adverse events were seen. CONCLUSIONS: In DMARD-naive early RA patients, initial therapy with MTX+high-dose intravenous steroid resulted in good disease control with little structural damage. MTX+IFX was not statistically superior to MTX+intravenous steroid when combined with a treat-to-target approach.

Multinational evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative.

OBJECTIVE: To develop evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis (UPIA). METHODS: 697 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2008-9 consisting of three separate rounds of discussions and modified Delphi votes. In the first round 10 clinical questions were selected. A bibliographic team systematically searched Medline, Embase, the Cochrane Library and ACR/EULAR 2007-2008 meeting abstracts. Relevant articles were reviewed for quality assessment, data extraction and synthesis. In the second round each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. RESULTS: A total of 39,756 references were identified, of which 250 were systematically reviewed. Ten multinational key recommendations about the investigation and follow-up of UPIA were formulated. One recommendation addressed differential diagnosis and investigations prior to establishing the operational diagnosis of UPIA, seven recommendations related to the diagnostic and prognostic value of clinical and laboratory assessments in established UPIA (history and physical examination, acute phase reactants, autoantibodies, radiographs, MRI and ultrasound, genetic markers and synovial biopsy), one recommendation highlighted predictors of persistence (chronicity) and the final recommendation addressed monitoring of clinical disease activity in UPIA. CONCLUSIONS: Ten recommendations on how to investigate and follow-up UPIA in the clinical setting were developed. They are evidence-based and supported by a large panel of rheumatologists, thus enhancing their validity and practical use.

Retinoic acid induces embryonal carcinoma cells to differentiate into neurons and glial cells.

Murine embryonal carcinoma cells can differentiate into a varied spectrum of cell types. We observed the abundant and precocious development of neuronlike cells when embryonal carcinoma cells of various pluripotent lines were aggregated and cultured in the presence of nontoxic concentrations of retinoic acid. Neuronlike cells were also formed in retinoic acid-treated cultures of the embryonal carcinoma line, P19, which does not differentiate into neurons in the absence of the drug. The neuronal nature of these cells was confirmed by their staining with antiserum directed against neurofilament protein in indirect immunofluorescence experiments. Retinoic acid-treated cultures also contained elevated acetylcholinesterase activity. Glial cells, identified by immunofluorescence analysis of their intermediate filaments, and a population of fibroblastlike cells were also present in retinoic acid-treated cultures of P19 cells. We did not observe embryonal carcinoma, muscle, or epithelial cells in these cultures. Neurons and glial cells appeared in cultures exposed to retinoic acid for as little as 48 h. We found no evidence for retinoic acid toxicity, suggesting that the effect of the drug was to induce the development of neurons and glia rather than to select against cells differentiating along other developmental pathways.

Modeling the variability of insulin sensitivity for people with Type 1 Diabetes based on clinical data from an artificial pancreas study.

Type 1 Diabetes is an autoimmune disease that eliminates endogenous insulin production. Without the crucial hormone insulin, which is necessary to equilibrate the blood glucose level, the patient must inject insulin subcutaneously. Treatment must be personalized (timing and size of insulin delivery) to achieve glycaemic equilibrium and avoid long-term comorbidities. Patients are educated on Functional Insulin Therapy (FIT) in order to independently adjust insulin delivery several times a day (at least prior to each meal and physical activity). Among personalized parameters, the Correction Factor is used to occasionally correct hyperglycemia via the injection of an insulin dose (bolus) and its value determines the bolus size. Although well-known in common diabetes practice for chronically poorly controlled patients, the phenomenon of "hyperglycemia induces insulin resistance" on a short term basis in patients with rather well controlled diabetes is presented here. Using a new database of evidence, we show that the insulin sensitivity factor, depends on the current level of glycaemia. This opens the door to refining dosing rules for patients and insulin delivery devices in artificial pancreas systems.

Retinoic acid-induced neural differentiation of embryonal carcinoma cells.

We have previously shown that the P19 line of embryonal carcinoma cells develops into neurons, astroglia, and fibroblasts after aggregation and exposure to retinoic acid. The neurons were initially identified by their morphology and by the presence of neurofilaments within their cytoplasm. We have more fully documented the neuronal nature of these cells by showing that their cell surfaces display tetanus toxin receptors, a neuronal cell marker, and that choline acetyl-transferase and acetyl cholinesterase activities appear coordinately in neuron-containing cultures. Several days before the appearance of neurons, there is a marked decrease in the amount of an embryonal carcinoma surface antigen, and at the same time there is a substantial decrease in the volumes of individual cells. Various retinoids were able to induce the development of neurons in cultures of aggregated P19 cells, but it did not appear that polyamine metabolism was involved in the effect. We have isolated a mutant clone which does not differentiate in the presence of any of the drugs which are normally effective in inducing differentiation of P19 cells. This mutant and others may help to elucidate the chain of events triggered by retinoic acid and other differentiation-inducing drugs.

Potentials for lymphoid differentiation by cells from long term cultures of bone marrow.

Dexter has described a culture system in which pluripotent stem cells (CFUs) are maintained for several months on an adherent layer derived from bone marrow. The population of cells floating in the supernatant medium contains stem cells and other cells at later stages of myeloid differentiation. Mature lymphocytes have not been observed in these cultures. Since the culture conditions may select for stem cells restricted to myeloid differentiation, we have studied the differentiative potential of cultured stem cells. Cultures were established using various combinatins of CBA bone marrow and CBA/HT6T6 bone marrow to distinguish between adherent layer derived cells and "recharge" derived cells. After various intervals in culture, cells were injected into irradiated recipients of either CBA or CBA/HT6T6 genotype. Three to four months after reconstitution, mitotic spreads were prepared from proliferating lymphoid and myeloid cells. The results showed that cells capable of giving rist to both B and T lymphoid progeny were maintained in culture for six weeks. The origin of the nonadherent CFUs in these cultures were also examined. They were derived from both the adherent and the "recharge" cell populations.

Ineffectiveness of hepatitis B vaccination in cirrhotic patients waiting for liver transplantation.

Cirrhotic patients who undergo liver transplantation are at risk of acquiring de novo hepatitis B virus (HBV) infection at the time of transplantation. It is common practice to immunize these patients against HBV, but the efficacy of vaccination is uncertain. The response to vaccination with a recombinant HBV vaccine was examined in 49 patients with cirrhosis before liver transplantation. Patients received three doses (20 mg) of Engerix-B (SmithKline Beecham) at zero, one and two months before transplantation, and their response was measured on the day of liver transplantation (9.3+/-1.2 months after the initial dose of vaccine). Results were compared with those reported in healthy adults vaccinated according to the same schedule. Fourteen of 49 cirrhotic patients (28%) developed antibodies to hepatitis B surface antigen (anti-HBs) levels of more than 10 U/L after vaccination compared with 97% of healthy controls. Four patients (8%) had anti-HBs levels of more than 100 U/L compared with 83% in healthy individuals. Mean anti-HBs titre in the 14 responders was 62 U/L compared with 348 U/L in controls. No factor was identified that predicted response to vaccination. One of 49 patients acquired de novo HBV infection at the time of liver transplantation. Current HBV vaccination of cirrhotic patients waiting for liver transplantation is ineffective, and new strategies need to be developed to increase the response rate.

Ultrasound-enhanced diffusion through isolated frog skin.

The effect of ultrasound on the transport of oxygen across excised frog abdominal skin has been studied. Samples were mounted in an exposure chamber in which the Ringer's solution on one side was saturated with oxygen while the other side of the skin had a low initial oxygen concentration. They were treated with ultrasound at 1, 1.5 and 2 W cm-2 SATA c.w., respectively, and increases in the rate of oxygen transport were observed at all intensities. These increases ranged from 38 +/- 4% at 1 W cm-2 to 55 +/- 8% at 2 W cm-2. Variation in the pulse lengths from 25 to 200 ms and a constant average intensity did not affect the rate of transport significantly provided that the temporal intensity was constant. Since the peak acoustic pressure within the pulse increased with decreasing pulse length and increasing acoustic pressure increases the probability of cavitation occurring, the mechanism responsible for this phenomenon is probably not cavitation.

[Treatment centres and specialized clinics of the Centre hospitalier Robert-Giffard.]. / Traiter en ville. Les centres de traitement et cliniques spécialisées du Centre hospitalier Robert-Giffard.

The authors describe the evolution of certain mental health services of the Centre hospitalier Robert-Giffard : treatment centres, specialized clinics as well as treatment services implemented in the community. The authors identify the principles that have presided over the organization of these treatement.

Four-hour acetaminophen concentration estimation after ingested dose based on pharmacokinetic models.

INTRODUCTION: The United Kingdom has recently changed the indications for N-acetylcysteine treatment for acetaminophen intoxication. Any ingestion over 75 mg/kg is now referred to the hospital. A model based on pharmacokinetic parameters was developed to predict 4-h acetaminophen concentration for this and other ingested doses. METHODOLOGY: EMBASE and Medline were searched to obtain values for volume of distribution, absorption, and elimination constants and bioavailability for acetaminophen. Four-hour concentrations were calculated for ingestion doses currently recommended for hospital referral in different countries. Calculated plasma concentrations at 4 h for several doses were plotted against the Rumack-Matthew and the United Kingdom treatment lines. RESULTS: Six articles were used for the calculations (4 adult and 2 pediatric). In order to achieve a 4-h acetaminophen concentration of 100 mg/L, doses (mg/kg ± 99.9CI) of 180.5 ± 43.2 for adults and 396.1 ± 115.5 for children were calculated. DISCUSSION: A dose of 75 mg/kg would likely yield a 4-h acetaminophen concentrations well below 100 mg/L. Medical toxicologists and poison information specialists are left without evidence-based guidance for which patients or which ingestion history would now warrant referral to hospital for acetaminophen concentration measurement. Larger toxicokinetic studies in acetaminophen overdose are needed to define ingestion dose for referral to hospital.

Halothane 1.5 MAC, isoflurane 1.5 MAC, and the contractile responses of coronary arteries obtained from human hearts.

Active vasoconstriction of epicardial coronary arteries can cause myocardial ischemia in patients with coronary artery disease. Relief of vasoconstriction can improve blood flow to the heart. The purpose of this study was to determine if 1.5 MAC halothane and 1.5 MAC isoflurane would each attenuate contractions evoked by three putative mediators of coronary constriction in coronary arteries removed from the hearts of human beings. Hearts were obtained in the operating room from five patients undergoing cardiac transplantation and from six brain-dead patients undergoing organ donation procedures. Coronary arteries were dissected free, cut into rings, and studied in organ chambers. Endothelium-dependent relaxations to 10(-6) M bradykinin were examined; they indicated a variable degree of endothelial dysfunction in vessels used in the experiments. Contractile responses to 40 mM KCl were tested and were used as control contractions. Contractions evoked by serotonin, histamine, and prostaglandin F2 alpha were measured and were expressed as a percent of contractile responses evoked by 40 mM KCl. Halothane depressed the agonist-induced contractions. Maximal contractile responses to serotonin were 130% +/- 28% in untreated rings and 63% +/- 10% in rings exposed to halothane (P less than 0.03). Responses to histamine were 183% +/- 46% untreated and 121% +/- 26% during halothane administration (P less than 0.05), and responses to prostaglandin F2 alpha were 227% +/- 42% untreated and 148% +/- 18% with halothane (P less than 0.05). Isoflurane had no effect on contractions. The results demonstrate that 1.5 MAC halothane, but not 1.5 MAC isoflurane, attenuates contractile responses evoked by putative mediators of coronary vasoconstriction in coronary arteries removed from the hearts of human beings.

Anaesthetic management of an adolescent for scoliosis surgery with a Fontan circulation.

Advances in the treatment of congenital heart disease have led to a new group of adolescents or adults patients with cardiac anomalies. The anaesthetic management of these patients can be challenging especially when they are scheduled for major noncardiac surgery inducing haemodynamic instability. We report the case of a 14-year-old boy scheduled for posterior spinal fusion for idiopathic scoliosis who underwent a Fontan operation in infancy for pulmonary atresia with right ventricle hypoplasia. The preoperative investigations and the anaesthetic management are described.

Patient-controlled analgesia after spinal fusion for idiopathic scoliosis.

One hundred adolescents undergoing posterior spinal fusion for scoliosis were reviewed to assess the adequacy of postoperative patient-controlled analgesia. There were 94 females and 6 males. The mean settings for morphine dosage were a loading dose of 114.5 micrograms.kg-1, a bolus dose of 24.8 micrograms.kg-1, and a lockout interval of 9.9 minutes. This was used for an average of 75.8 h, with a 52.2% success rate. Adolescents using patient-controlled analgesia showed a great variability in morphine requirements with greater use as they became older. The requirement was not significantly different on the 1st, 2nd and 3rd postoperative days and the total consumption was 52.2 micrograms.kg-1.h-1. Nausea and vomiting occurred in 45% and pruritus in 15%. There were 7 cases of respiratory depression who all recovered promptly and completely. This method is associated with high morphine requirements in adolescents, but can be used safely.

Pain evaluation in preschool children and by their parents.

The accurate assessment of pain in children constitutes a challenge for health professionals and, in the case of young children, parents are generally the main source of information. The objective of this study was to validate and to compare three pain scales in preschool children and their parents. A total of 104 children between 4 and 6 y of age and their parents participated in the study while undergoing an immunization procedure in the outpatient department of a tertiary pediatric care hospital. Three pain scales were used, the McGrath Facial Affective Scale (FAS), the Hester Poker Chip Tool (HPCT) and the Multiple Size Poker Chip Tool (MSPCT). There were 47 (45%) boys and 57 (55%) girls, with 54 (52%) 4-y-olds, 34 (33%) 5-y-olds and 16 (15%) 6-y-olds. Twenty-eight children (27%) had memories of pain experienced during a former hospitalization. Correlations were very high both in children (r = 0.78) and their parents (r = 0.96) when comparing immunization pain scores obtained from the HPCT versus the MSPCT. Correlations between McGrath's FAS and HPCT or MSPCT ranged from r = 0.34-0.43 in children and r = 0.38-0.39 in parents. There was a good correlation between parents and children during the immunization procedure on all three scales, with the highest correlation using the FAS (r = 0.76), followed by the MSPCT (r = 0.69), and the HPCT (r = 0.66). Subgroup analyses based on the criteria of age, sex and previous hospitalization showed no consistent relationship. Parents tended to underestimate their child's pain when using HPCT or MSPCT. It seems that both HPCT and MSPCT measure a similar dimension of pain, whereas the FAS addresses a different aspect of pain. Although parents play an important role in their child's pain assessment, they tend to underestimate the intensity of pain when using HPCT or MSPCT.

Effects of isoflurane, halothane, and enflurane on myocardial flow and energy stores in the perfused rat heart.

The effect of three volatile anesthetics (halothane, enflurane, and isoflurane) on coronary flow and metabolic state of isolated rat hearts was studied. These anesthetics are coronary dilators and their effects are dose dependent. At 2 MAC (minimum alveolar concentration), isoflurane, enflurane, and halothane increase coronary flow by 114 +/- 5.9, 93 +/- 6.1, and 77 +/- 6.4%, respectively (p less than 0.001). At these concentrations, they also have a modest but significant metabolic effect causing a 30% reduction in myocardial ATP and phosphocreatine levels, with no significant modification in ADP and AMP concentrations. Energy charge and lactate/pyruvate ratio were also unaffected by these anesthetics. The vascular and metabolic effects were reversible within 2 and 30 min, respectively. Perfusion of the hearts with a Krebs-Henseleit solution without Pi did not interfere with the vascular and the metabolic effect of the anesthetics; however, in this case, ATP and phosphocreatine concentration did not return to control levels after their discontinuation despite full recovery of the vascular effect. These data suggest that the volatile anesthetics have direct coronary vascular and myocardial metabolic effects and that these effects occur independently.