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.

On-line measurement of texture, thickness and plastic strain ratio using laser-ultrasound resonance spectroscopy.

Laser-ultrasound resonance spectroscopy, a non-contact ultrasonic technique, was used to determine reliably and rapidly the crystallographic texture, the average plastic strain ratio, and the thickness of sheet metal on the production line. As with laser-ultrasonics, a short laser pulse is used to generate a wide-band pulse of ultrasound and a laser interferometer is used for its detection. In this paper, a large number of echoes are collected and analyzed together using Fourier techniques to measure the natural resonance frequencies in the thickness of the sheet. One longitudinal and two shear resonance frequencies were measured together with their harmonics. From these frequencies, two crystallographic orientation distribution coefficients, W(400) and W(420), are obtained, as well as a highly accurate measurement of the sheet thickness that is corrected for changes in ultrasonic velocity caused by texture variations. Using these coefficients, the average and in-plane twofold and fourfold variations of the plastic strain ratio, respectively r delta(2)r, and delta(4)r, can be evaluated. These parameters are indications of the formability of metals sheets, which is of industrial interest. Measurements on 1 mm thick, low carbon steel sheets have shown the following measurement accuracies: r to within +/-0.08, delta(2)r, and delta(4)r to within +/-0.1, and thickness to better than +/-1 microm. On-line tests at LTV Steel Company showed that the sensitivity of the apparatus is sufficient to detect systematic variations in texture along the length of similar production coils and that the on-line repeatability for r was of order +/-0.02.

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.

Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety.

Apo2L/TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a member of the tumor necrosis factor gene family known to induce apoptosis in a number of cancer cell lines and may have broad-spectrum activity against human malignancies. These studies have evaluated the potency of recombinant soluble human Apo2L/TRAIL in a mouse xenograft model and the disposition and safety of Apo2L/TRAIL in rodents and nonhuman primates. Mice with established COLO205 tumors were given daily i.v. injections of Apo2L/TRAIL (30-120 mg/kg/day). Control tumors doubled in size every 2 to 3 days, while time to tumor doubling in the treatment groups was significantly longer and related to dose (14-21 days). For pharmacokinetic studies, Apo2L/TRAIL was given as an i.v. bolus to mice (10 mg/kg), rats (10 mg/kg), cynomolgus monkeys (1, 5, and 50 mg/kg), and chimpanzees (1 and 5 mg/kg). Apo2L/TRAIL was rapidly eliminated from the serum of all species studied. Half-lives were approximately 3 to 5 min in rodents and approximately 23 to 31 min in nonhuman primates. Allometric scaling provided estimates of Apo2L/TRAIL kinetics in humans, suggesting that on a milligram per kilogram basis, doses significantly lower than those used in xenograft studies could be effective in humans. Apo2L/TRAIL clearance was highly correlated with glomerular filtration rate across species, indicating that the kidneys play a critical role in the elimination of this molecule. Safety evaluations in cynomolgus monkeys and chimpanzees revealed no abnormalities associated with Apo2L/TRAIL exposure. In conclusion, these studies have characterized the disposition of Apo2L/TRAIL in rodents and primates and provide information that will be used to predict the pharmacokinetics of Apo2L/TRAIL in humans.

[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.

Safety and antitumor activity of recombinant soluble Apo2 ligand.

TNF and Fas ligand induce apoptosis in tumor cells; however, their severe toxicity toward normal tissues hampers their application to cancer therapy. Apo2 ligand (Apo2L, or TRAIL) is a related molecule that triggers tumor cell apoptosis. Apo2L mRNA is expressed in many tissues, suggesting that the ligand may be nontoxic to normal cells. To investigate Apo2L's therapeutic potential, we generated in bacteria a potently active soluble version of the native human protein. Several normal cell types were resistant in vitro to apoptosis induction by Apo2L. Repeated intravenous injections of Apo2L in nonhuman primates did not cause detectable toxicity to tissues and organs examined. Apo2L exerted cytostatic or cytotoxic effects in vitro on 32 of 39 cell lines from colon, lung, breast, kidney, brain, and skin cancer. Treatment of athymic mice with Apo2L shortly after tumor xenograft injection markedly reduced tumor incidence. Apo2L treatment of mice bearing solid tumors induced tumor cell apoptosis, suppressed tumor progression, and improved survival. Apo2L cooperated synergistically with the chemotherapeutic drugs 5-fluorouracil or CPT-11, causing substantial tumor regression or complete tumor ablation. Thus, Apo2L may have potent anticancer activity without significant toxicity toward normal tissues.

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.