Colchicine for postoperative pericardial effusion: a multicentre, double-blind, randomised controlled trial.

OBJECTIVES: Pericardial effusion is common after cardiac surgery. Growing evidence suggests that colchicine may be useful for acute pericarditis, but its efficacy in reducing pericardial effusion volume postoperatively has not been assessed. METHODS: This randomised, double-blind, placebo-controlled study conducted in 10 centres in France included 197 patients at high risk of tamponade (ie, with moderate to large-sized persistent effusion (echocardiography grades 2, 3 or 4 on a scale of 0-4)) at 7-30 days after cardiac surgery. Patients were randomly assigned to receive colchicine, 1 mg daily (n=98), or a matching placebo (n=99). The main end point was change in pericardial effusion grade after 14-day treatment. Secondary end points included frequency of late cardiac tamponade. RESULTS: The placebo and the colchicine groups showed a similar mean baseline pericardial effusion grade (2.9±0.8 vs 3.0±0.8) and similar mean decrease from baseline after treatment (-1.1±1.3 vs -1.3±1.3 grades). The mean difference in grade decrease between groups was -0.19 (95% CI -0.55 to 0.16, p=0.23). In total, 13 cases of cardiac tamponade occurred during the 14-day treatment (7 and 6 in the placebo and colchicine groups, respectively; p=0.80). At 6-month follow-up, all patients were alive and had undergone a total of 22 (11%) drainages: 14 in the placebo group and 8 in the colchicine group (p=0.20). CONCLUSIONS: In patients with pericardial effusion after cardiac surgery, colchicine administration does not reduce the effusion volume or prevent late cardiac tamponade. CLINICAL TRIAL REG NO: NCT01266694.

T-cell-dependent antibody responses in the rat: forms and sources of keyhole limpet hemocyanin matter.

The T-cell-dependent antibody response (TDAR) is a functional assay used in immunopharmacology and immunotoxicology to assess ability to mount an antibody response to immunization. Keyhole limpet hemocyanin (KLH) is extensively used as the immunogen of choice in non-clinical and clinical settings. Native KLH is comprised of high molecular weight (HMW; 4-8 MDa) assemblies of KLH subunit dimers (> 600-800 kDa). It is not known how the different forms (HMW vs subunit) and manufacturing processes (commercial sources) may impact the nature of anti-KLH immune responses (e.g. magnitude and inter-animal variability). Anti-KLH IgM and IgG responses were studied in Sprague-Dawley rats immunized with different forms and commercial sources of KLH: 100 µg of HMW KLH from two different sources or subunit KLH from three different sources. Biophysical and biochemical analyses were conducted to characterize the KLH formulations. Anti-KLH IgM and IgG responses were measured using a proprietary indirect quantitative electrochemiluminescence immunoassay. The HMW KLH preparations showed a greater number of sub-visible particles (2-150 µm size range) than the subunit KLH preparations. All HMW KLH and all subunit KLH were equivalent on SEC (hydrodynamic volume), PAGE (size and charge), and SDS-PAGE (molecular radius). Robust primary and secondary anti-KLH responses were detected for both sources of HMW KLH. The subunit KLH immunizations resulted in lower IgG and IgM responses compared to the HMW KLH, with the exception of Stellar Biotechnologies subunit KLH that produced both robust primary and secondary responses, which approached the HMW KLH responses. Inter-animal variability for IgM and IgG responses was lower with HMW KLH than with subunit KLH. In conclusion, different forms and commercial sources of KLH were associated with different magnitudes and inter-animal variability in IgM and IgG responses, a critical finding to take into consideration when designing TDAR studies for robust immunotoxicology or immunopharmacology testing.

Animal models as indicators of immunogenicity of therapeutic proteins in humans.

Animal models have not been able to predict the immunogenicity of therapeutic proteins in humans reliably. The main issue is that administration of a human protein in an animal species is likely to be immunogenic. In non-human primate studies, we have seen a variety of responses; from little to no antibody response, to a strong neutralizing response, or even a cross-reactive antibody response. These have generally not correlated well with the immune response seen in humans. The route of administration, duration and schedule of dosing, the cumulative dosage of the protein, the pharmacological (i.e., immune altering) properties of the protein, as well as the purity of the clinical material can influence the immunogenicity. The animal studies should mimic these factors to the best extent possible for the animal model to be at all relevant to humans. Models do exist which provide valuable information to compare the immunogenicity of various compounds or routes of administration. Presumably, this 'relative' immunogenicity would be similar in humans. Additional characterization of transgenic mice, or use of homologous proteins, may help to establish better models to predict immunogenicity.

No changes in the distribution of organisms responsible for septic arthritis over a 20 year period.

OBJECTIVE: To assess changes in the distribution and resistance of the pathogens responsible for septic arthritis over a 20 year period in patients admitted to the same hospital unit. PATIENTS AND METHODS: Retrospective study of the hospital records of patients admitted between 1979 and 1998 for septic arthritis with positive microbiological diagnosis after blood or joint cultures, or both. RESULTS: 303 cases of septic arthritis were studied, 141 in the period 1979-88 and 162 in the period 1989-98. The incidence between the first and second period did not vary significantly for the staphylococci (67% v. 63%), streptococci (16% v. 20%), and Gram negative bacilli (7% v. 10%). Tuberculous infections decreased from 9% to 4% (p<0.04). No gonococci were isolated in the second 10 year period. Among the staphylococcal species, there was an increase in the number of coagulase negative staphylococci (10 cases v. 21, p<0.05) between the two periods. There was no significant difference in the frequency of occurrence of methicillin resistant pathogens (12.6% v. 16.6%). The number of streptococcal B infections increased (2 v. 10 cases), and beta-lactamine resistant pneumococci emerged. In the second 10 year period, patients were older and were more likely to have co-existing disease, particularly tumoral growth, and less commonly were receiving dialysis. Localisation of joint infection was comparable except for an increase in prosthetic knee infections. CONCLUSION: The distribution and sensitivity of pathogens causing septic arthritis changed little over a 20 year period.

Pamidronate in the treatment of diffuse sclerosing osteomyelitis of the mandible.

Diffuse sclerosing osteomyelitis of the mandible is characterized by bouts of intense pain, sometimes associated with trismus and paresthesia, and leads to progressive deformity. It is of unknown etiopathology, but it is suggested to be one manifestation of the synovitis, acne, pustulosis, hyperostosis, osteomyelitis syndrome, the other features of which may have been overlooked. Treatment results are disappointing, and decortication may be necessary to achieve an acceptable outcome. We report a case restricted to the mandible that responded favorably to treatment with pamidronate. Further trials of pamidronate in patients with diffuse sclerosing osteomyelitis of the mandible, even in those with the aforementioned syndrome, are needed to assess its effectiveness.

[Rheumatoid arthritis preceding microscopic polyangitis. Report of two cases]. / Polyarthrite, manifestation inaugurale d'une polyangéite microscopique. A propos de deux observations.

INTRODUCTION: Although joint manifestations are common in microscopic polyangiitis (MPA), including arthralgia reported in 15-65% of cases and arthritis in 6-17%, there have been only two published cases of polyarthritis as the first manifestation of the disease. We report on two new cases. EXEGESIS: A 71-year-old woman had symmetric polyarthritis of the hands which initially suggested the existence of seronegative rheumatoid arthritis. A 52-year-old woman had seropositive asymmetric oligoarthritis. The diagnosis was not established until renal insufficiency appeared, prompting a renal biopsy which showed in both cases an extra-capillary glomerulonephritis and an anti-myeloperoxydase (p-ANCA) assay which was postive in both patients. The incidence and specificity of antineutrophil cytoplasmic antibodies (ANCA), including MPA, in rheumatoid arthritis are reviewed. CONCLUSION: Our two observations show that in cases of polyarthritis or oligoarthritis with renal involvement, testing for and typing of ANCA should be performed so as not to misdiagnose vasculitis.

Lack of developmental neurotoxicity of MN rgp 120/HIV-1 administered subcutaneously to neonatal rats.

The potential for neurotoxic effects was evaluated in rat off-spring after exposure in utero and/or during the neonatal period to a recombinant subunit vaccine of gp120 prepared from the MN strain of HIV-1 (MN rgp 120/HIV-1). Thirty pregnant female rats were given MN rgp120/HIV-1 with alum adjuvant, and 30 rats were given vehicle, once every 3 days from Day 1 of presumed gestation until parturition. One pup/sex/litter from treated and control group dams were given a daily subcutaneous injection, from Day 1 through Day 22 postpartum (PP) of vehicle, MN rgp120/HIV-1, MN rgp120/HIV-1 with alum, or MN rgp120/HIV-1 with QS-21 adjuvant. Neurobehavioral and physical development were evaluated (preweaning reflex and development, sexual maturation, motor activity, acoustic startle, passive avoidance, functional observational battery, and water M-maze testing), and tissues were processed for anatomical examination (whole and regional brain weights, and neuropathology). Administration of MN rgp120/HIV-1, with or without adjuvant, to pups did not cause any persistent effect on any parameter evaluated. Neurohistological examination did not reveal any pathological effects related to treatment. Thus, MN rgp120/HIV-1 alone or formulated as a vaccine does not cause neurotoxicity or developmental toxicity in neonatal rats after exposure in utero and/or during the neonatal period.

The isometric force that induces maximal surface muscle deoxygenation.

To determine the external force that induces maximal deoxygenation of brachioradialis muscle 32 trained male subjects maintained isometric contractions using the elbow flexor muscles up to the limit time (isotonic part of the isometric contraction, IIC) and beyond that time for 120 s (anisotonic part of the isometric contraction). During IIC each subject maintained relative forces of either 25% and 70% maximal voluntary contraction (MVC), 50% and 100% MVC, or 40% and 60% MVC. Muscle oxygenation was assessed using a near infrared spectroscope, and expressed as a percentage of the reference value (deltaO2rest) which was the difference between the minimal oxygenation obtained after 6 min of ischaemia at rest and the maximal reoxygenation following the release of the tourniquet. During IIC at 25% MVC, muscle oxygenation decreased to 17 (SEM 3)% deltaO2rest, then it levelled off [25 (SEM 1)% deltaO2rest]. After the point at which target force could not be maintained, reoxygenation was very weak. During IIC at 40%, 50%, 60%, and 70% MVC, the lowest muscle oxygenation values were obtained after 15-20 s of contraction and corresponded to -18 (SEM 6), -59 (SEM 12) -31 (SEM 6), and -29 (SEM 6)% deltaO2rest, respectively. For the contraction at 100% MVC, the lowest oxygenation [-19 (SEM 9)% deltaO2rest] was obtained while force was decreasing (69% MVC). During the anisotonic part of the isometric contractions, the greatest reoxygenation rate was obtained after 50% MVC IIC (P < 0.001). Our results showed that during isometric elbow flexions between 25% and 100% MVC, there was no linear relationship between external force and muscle oxygenation, and that the maximal deoxygenation of the brachioradialis muscle was obtained at 50% MVC.

Vasculitis confined to the calves. Report of a case.

Polyarteritis nodosa is a systemic disease of which limited forms have been reported, with the most common involving the skin. Only 13 cases with lesions confined to the calves have been reported to date. We report a new case.

Response to minocycline of arthritis associated with agammaglobulinemia. A case-report.

Seven to 22% of patients with agammaglobulinemia develop joint manifestations consisting of septic arthritis or aseptic arthritis of unclear pathogenesis. Intravenous gammaglobulin therapy seems effective on the latter condition but is burdensome and expensive. We report the case of a patient with common variable immunodeficiency and aseptic oligoarthritis in which minocycline therapy was effective in relieving the joint symptoms.

[Giant aneurysm of the interventricular septum. Value of imaging techniques]. / Anévrisme géant du septum interventriculaire. Apport des techniques d'imagerie.

A pseudosubaortic left ventricular aneurysm was discovered in a 32 year old African presenting with pyrexia after a long history of chest pains and dyspnea. Echographic and radiological techniques showed a large pulsatile mediastinal mass and the patient was referred for aneurysmorrhaphy. The actiology of this pseudo-aneurysm is discussed with reference to data in the literature. Infection is the first cause to be excluded in view of the pyrexia truncated by "blind" anti-inflammatory and antibiotic therapy. The hypothesis of an interventricular septal abscess secondary to septicaemia with secondary rupture into the pericardium is discussed. Precessive endocarditis with an aseptic abscess is unlikely because of the minimal aortic valve lesions, the absence of vegetations and the very long clinical evolution. Finally, idiopathic pseudo-aneurysms in sub-Saharian Africans, due to a congenital defect of the fibrous aortico-mitral and subannular zones must be considered. The risk of complications of these pseudo-aneurysms justifies surgical intervention on the accurate anatomical description of the lesions provide by transthoracic and transoesophageal echocardiography and magnetic resonance imaging.

[Does reactive arthritis caused by Brucella exist? Apropos of 4 cases]. / Les arthrites réactionnelles à Brucella existent-elles? A propos de 4 observations.

OBJECTIVES: Arthritis observed in patients with Brucella infection is usually considered to result from live micro-organisms invading the synovia. We observed four cases of brucellosis in which the clinical and laboratory findings suggested a different mechanism: reactive arthritis. CLINICAL OBSERVATIONS: The diagnosis of brucellosis was made on the basis of serology tests in 3 patients and blood cultures in 1. All 4 patients presented oligoarthritis. The synovial fluid was sterile in 3. Antibiotics were ineffective in reducing joint pain and inflammation whereas local and systemic anti-inflammatory drugs were effective. Three patients also had other manifestations (sausage-shaped toes, talalgia, sacroiliitis) and fulfilled the diagnostic criteria for spondylarthropathy. All patients were positive for antigen HLA-B27. DISCUSSION: These observations suggest that Brucella should be added to the list of intracellular infectious agents capable of inducing reactive arthritis, despite the lack of all the diagnostic criteria. For some, such as the uretritis or diarrhea observed before joint involvement, it would be difficult to implicate the germ. Brucella serology should be part of the etiology work-up for reactive arthritis in endemic areas.

An open study of the anti-TNF alpha agent pentoxifylline in the treatment of rheumatoid arthritis.

OBJECTIVE: Monoclonal antibodies to TNF alpha have a rapid therapeutic effect in rheumatoid arthritis. Pentoxifylline is an anti-TNF alpha agent that is easier to handle than antibodies. METHODS: An open prospective trial was conducted in 21 patients with active rheumatoid arthritis. Pentoxifylline was given in a daily dosage of 1,200 mg for at least one month. Five patients received the drug as a continuous intravenous infusion during the first seven days. RESULTS: After one month, a significant decrease in the pain severity score was noted, but all other clinical and laboratory efficacy parameters were unchanged. A limited response was seen in four patients. TNF alpha levels did not decrease under therapy. CONCLUSION: Under the conditions of our trial, the therapeutic benefits provided by pentoxifylline were too small to warrant use of this drug in severe refractory rheumatoid arthritis.

Subchondral insufficiency fracture of the femoral head.

We report two cases of subchondral insufficiency fractures of the femoral head. Clinical manifestations of this lesion are nonspecific. Radionuclide bone scanning demonstrates early hyperactivity. Initial roentgenograms are usually normal. Magnetic resonance imaging establishes the diagnosis and rules out other conditions.

Reproductive effects of chronic administration of murine interferon-gamma.

Daily subcutaneous doses of 0.02, 0.2, or 2 mg/kg/d of recombinant murine interferon-gamma (rmuIFN-gamma) were given to mice on postnatal days 8 through 60 to determine effects on maturation, behavioral/ functional development, and reproductive capacity. Male mice receiving 2 mg/kg/d rmuIFN-gamma had delayed sexual maturation, reduced epididymal and testes weights, reduced sperm count and concentration, and sperm abnormalities (crimped flagellum). Mating performance and fertility were also reduced in the absence of altered histopathology of the testes. Males given 0.2 and 2 mg/kg/d had swelling and ulcerative dermatitis around the urogenital area, which were observed after sexual contact and attributed to a bacterial infection. Motor activity (time spent in movement) was decreased in all mice receiving 2 mg/kg/d. No microscopic changes observed in any organs were attributed to rmuIFN-gamma administration.

[Is plasma lipoprotein (a) level a reliable indicator predicting restenosis after angioplasty?]. / Le taux plasmatique de lipoprotéine (a) permet-il de prédire la resténose après angioplastie?

Lipoprotein (a) [Lp(a)] is an independent genetically determined marker of coronary artery disease. It is present in the atheromatous plaque with a molecular structure similar to that of plasminogen. Its role in postangioplasty restenosis is a possibility but is controversial. A population of 103 coronary patients underwent angioplasty with control coronary angiography before the 6th month; there were 53 good results and 50 cases of restenosis. The Lp(a) was measured by immunonephelemetry (threshold value of 250 mg/l). A subgroup with Lp(a) concentrations > 250 mg/l was identified. The average concentrations of Lp(a) in the two groups without restenosis (368 +/- 350 mg/l) and with restenosis (418 +/- 434 mg/l) were not statisticaly different (p = 0.2). When cases with Lp(a) > 250 mg/l were considered alone, the tendency to higher average concentrations of Lp(a) in the group with restenosis (777 +/- 424 mg/l) compared with the group without restenosis (656 +/- 340 mg/l) was more clear-cut but did not achieve statistical significance (p = 0.08). The individual scatter of Lp(a) being very wide (83 to 1,450 mg/l in the group without restenosis and 90 to 1,740 mg/l in the group with restenosis), it is impossible to predict restenosis from this parameter in a given individual. No correlations were observed between the different lipid fractions and restenosis. The extension of the lesions and the angioplasty site did not correlate with restenosis in this study. The authors conclude: 1) that the Lp(a) concentration has no individual predictive value for restenosis; 2) individuals with Lp(a) concentrations > 250 mg/l have an increased risk of restenosis (NS); 3) these results confirm other recent publications; and 4) further research into the isoforms of Lp(a) in each group could provide interesting data.

[Prognosis of multiple myeloma treated with conventional chemotherapy has not improved in 20 years]. / Le pronostic du myélome traité chimiothérapie conventionnelle ne s'est pas amélioré en 20 ans.

The treatment of multiple myeloma has changed over the last 20 years. We investigated the effects of theses changes on patient survival in the current practice of a rheumatology ward. Two hundred and seventy-nine patients were hospitalised between 1972 and 1993: 30 from 1972 to 1976, 70 from 1977 to 1981, 86 from 1982 to 1986, 75 from 1987 to 1991 and 18 from 1992 to 1993. Staging according to Durie and Salmon was I in 8%, II in 29% and III in 65%. In principle, the initial therapy was monochemotherapy in 65% of the cases and polychemotherapy in 35%. At the time of the present study, 197 patients have died. The actuarial curves of survival were similar in all historical classes defined by the date of first admission. Curves of median of follow-up and of floating means were level between 1972 and 1990. No correlation was found between the date of first admission and survival in the 174 patients who died between 1972 and 1987. The following parameters were associated with longer survival: achievement of an objective response on chemotherapy, lower patient's age, high haemoglobin, low creatinine, low stage according to Durie and Salmon, low number of plasma cells in bone marrow, low calcemia and low levels of IgA, monoclonal component. The comparison of prognosis factors in historical classes showed a difference only for haemoglobin which was lower in the earlier class. The type of the first chemotherapy regimen varied widely between historical classes. The number of responders was significantly greater after polychemotherapy than after monochemotherapy but no correlation was observed between the type of chemotherapy and survival. The frequencies of early death, and the causes of death in general, were not different in the historical classes. The lack of improvement of survival over the last 20 years shows that the efficacy of current chemotherapies is limited, a conclusion which warrants the exploration of other therapeutic avenues.