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.

Polyarticular septic arthritis.

Twenty-five cases of polyarticular septic arthritis (PASA) were observed in our department over a 13-year period. They accounted for 16.6% of all septic arthritis (15% on average in the literature). A male predominance was noted in our patients, as well as in the literature. The knee was the most frequent location followed by the elbow, shoulder, and hip, in varying order depending on the series. An average of 4 joints was involved. The causative microorganism was Staphylococcus aureus in 20/25 of our patients and in about 50% of published cases. Other frequently causative organisms were streptococci and gram-negative bacteria. Blood cultures and joint aspirations were positive in 19/22 and 23/25 of our cases, respectively. Other septic lesions were noted in 10/25 of our cases. Fever and severe leukocytosis were absent at admission in 5/25 (literature, 37%) and 10/25 of our 25 patients, respectively. The underlying disease was rheumatoid arthritis in 13/25, while 9 of the other patients had immunodepression caused by drugs or by concurrent illness. Typically, rheumatoid arthritis was long-standing and erosive, patients having ulcerated calluses on the feet. This skin source was also noted in 23/36 published cases of PASA in rheumatoid arthritis. Systemic lupus erythematosus was an uncommon disease in PASA, but its presence promoted gram-negative infection. Despite effective therapy with 2 antibiotics, 8/25 patients died, a prognosis that is equally severe in cases reported in the literature (30%) and one that has remained surprisingly stable over the last 40 years. For comparison, the death rate was only 4% in our patients with MASA. Factors contributing to a poor prognosis were age greater than 50 years, rheumatoid arthritis as an underlying disease, and disease of staphylococcal origin. Septic polyarthritis should be considered even when the clinical picture is not florid--when patients have low fever and normal white blood cell counts. Nor should the simultaneous involvement of distant joints rule out infection. Indeed, the frequency of underlying rheumatic disease and its treatment may further confuse the clinical presentation. Joints suspected of harboring infection should be aspirated, including those previously affected by the concurrent rheumatism.

Effect of cyclosporine on 3-methylcholanthrene-induced carcinogenesis and immune responses in the rat.

Cyclosporine A (CsA) was used to immunosuppress male Sprague-Dawley rats treated with the chemical carcinogen 3-methylcholanthrene (3MC). Rats treated with low doses of CsA (2.5 or 5 mg/kg) given 2 days prior to an injection of 3MC, and then daily for 2 weeks or twice weekly for 10 weeks did not develop tumors. Rats treated with 2.5 mg/kg CsA for 2 weeks beginning 5 days after a single 3MC injection had tumor incidence similar to rats treated with 3MC only. To further examine the effects of CsA on immune function, groups of rats were then treated with 2.5, 5, 10 or 20 mg/kg CsA daily for 14 days and immune function assessed by measuring delayed-type hypersensitivity (DTH), natural killer cell (NK) activity, and production of interleukin 2 (IL-2), interferon (IFN), prostaglandin E2 (PGE2) and specific IgG antibody. Natural killer cell cytotoxicity was enhanced and antibody production was suppressed in rats treated with all doses of CsA tested. Interleukin 2 production was elevated at the two lower doses, but antibody production, DTH reactions and synthesis of IL-2 and IFN were suppressed with the higher dose treatments (10, 20 mg/kg CsA). The enhanced NK activity seen in rats treated with the lower doses of CsA may be due to the increase in IL-2 production, while enhancement of NK activity at higher doses may be due to other mechanisms. The tumor data suggest that CsA does not prevent tumor formation in our chemical-induced model due to an increase in NK activity, since this enhancement was seen even when tumors did develop normally.

Intraoperative coronary artery endarterectomy with excimer laser.

Compared with continuous-wave lasers, excimer lasers exhibit several in vitro advantages: nonthermal ablation process and linear relation between the number of pulses and the depth of the crater. A 308 nm, 20 nsec pulse duration, 1 to 5 repetition rate laser was specifically designed for clinical application. At the time of cardiopulmonary bypass in 10 symptomatic patients, before bypass grafting, a 1 mm diameter core specifically ultraviolet-tipped fiberoptic scope was introduced via the coronary arteriotomy and placed upstream (seven patients) and downstream (three patients) in contact with the stenosis. Laser power was increasingly delivered up to the clearing of the stenosis or occlusion. Quality of angioplasty was controlled by calibration of the neolumen, cardioplegic solution output through the laser-treated segment, and an eighth day or sixth month coronary arteriogram. In the first three patients studied on the eighth day, all laser-treated coronary artery segments showed an early parallel-linked patent neolumen despite competitive bypass graft flow. In the patients studied after 6 months, all recanalized segments were patent except one; in one patient the venous graft was occluded, but the upstream laser angioplasty was patent. The main limitation of the method lies in the fact that laser coronary recanalization is confined to the fiber core diameter. We conclude that (1) excimer laser angioplasty may be safe and efficient during surgical procedure and (2) as catheter flexibility remains the most critical problem, we are now assuming an appropriate tool with a multifiber system that is suitable for intraoperative as well as percutaneous routes.

Comparison of treadmill and bicycle exercise in patients with chronic heart failure.

The general opinion that treadmill exercise elicits circulatory reserve more than bicycle exercise derives from studies conducted in normal subjects or subjects with coronary artery disease. To investigate if this also occurs in patients with chronic heart failure (CHF), 40 patients (mean ejection fraction: 26 +/- 9 percent) with normal pulmonary function underwent in random order both treadmill (Naughton modified protocol, holding on handrails permitted) and bicycle (10 W/min) maximal exercise over a 1-week period. Peak oxygen uptake (19.6 +/- 5.3 vs 17.6 +/- 5.1 ml/min/kg, p < 0.0001), ventilatory threshold (14.4 +/- 4.7 vs 12.0 +/- 3.5 ml/min/kg, p < 0.0001), and minute ventilation (59 +/- 18 vs 55 +/- 15 L/min, p < 0.05) were greater on treadmill than on bicycle. Heart rate, systolic blood pressure, breathing rate, respiratory exchange ratio, perceived exertion scale, and lactate were identical. The coefficient of the correlation between oxygen uptake and time was greater with bicycle than with treadmill (r = 0.97 +/- 0.04 vs 0.90 +/- 0.07, p < 0.001). Thus, treadmill exercise is more suitable for determining peak oxygen uptake in patients with CHF. However, the increase in oxygen uptake is more regular with bicycle exercise.

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.

Pyrogenic doses of intracerebroventricular interleukin-1 did not induce analgesia in the rat hot-plate or cold-water tail-flick tests.

There are a few reports in the literature that cytokines can induce analgesia (5, 6, 18). The present study sought to characterize the analgesic effects of intracerebroventricularly (icv) administered interleukin-1 (IL-1) and interferon-alpha (IFN-alpha) in rats. In the cold-water tail-flick test (CWT), latency to tail withdrawal from a -3 degrees C liquid was timed; in the hot-plate test (HP), latency to a rear paw lick or a jump from a 55 degrees C surface was measured. In some experiments, core body temperature was also monitored with a rectal thermistor. In the CWT, human recombinant (hr) IFN-alpha induced a small, statistically significant effect at just one dose (15,000 U icv), but no dose of hr-IL-1 alpha (250-1000 U icv) or hr-IL-1 beta (125-2000 U icv) induced a significant effect at any time point. On the other hand, dose-related increases in body temperature were observed after icv injection of both IL-1 alpha and IL-1 beta. The largest hyperthermic effect was a 1.7 (+/- 0.15) degrees C rise 120 min after administration of 1000 U IL-1 beta. In a second analgesic assay, the HP, IL-1 beta was ineffective as well. Since IL-1 alone did not induce analgesia, we tested its capacity to potentiate morphine analgesia. Morphine (5.0 and 10 micrograms, icv) induced analgesia in the CWT (32.7 and 61.8% maximum analgesia, respectively); however, there was no significant effect of IL-1 beta on morphine-induced analgesia. In summary, we failed to find an analgesic effect of IL-1, alone or in combination with morphine, at doses which clearly had a physiological effect; this is in contrast to the reports cited above.

Morphine treatment in vitro or in vivo decreases phagocytic functions of murine macrophages.

Studies were performed to compare in vitro and in vivo effects of morphine on the phagocytic function of murine peritoneal macrophages. Macrophage monolayers were incubated with Candida albicans for 30 min in the absence of autologous serum. Morphine added in vitro was found to decrease both the phagocytic activity (percent of phagocytic cells) and the phagocytic index (average number of ingested yeasts per cell) in a concentration-dependent manner, with maximal effects of 26% and 41%, respectively, at 10(-6) M. When morphine was administered in vivo via an implanted 75-mg pellet, there was a 22% decrease in phagocytic activity and a 40% decrease in the phagocytic index. Naltrexone completely blocked the effects of morphine both in vitro and in vivo. The results suggest that morphine is capable of interacting directly with opioid receptors on macrophages, resulting in a decrease in phagocytic function.

Effects of in vivo morphine treatment on antibody responses in C57BL/6 bgJ/bgJ (beige) mice.

C57BL/6J bgJ/bgJ (beige) mice are less sensitive than other strains to the analgesic effects of morphine, although they have normal numbers of mu receptors. In the present study, beige mice and their normal littermates (beige+) were treated in vivo with morphine or the opioid antagonist, naltrexone and their primary in vitro antibody responses were assessed. Morphine treatment caused splenic atrophy and suppressed the primary in vitro antibody response in beige and beige+ mice. However, these effects were not blocked by naltrexone co-treatment. In these mouse strains, naltrexone decreased spleen size and antibody responses by itself, which may mask its ability to antagonize morphine. In beige mice, placebo pellet implantation suppressed the primary in vitro antibody response. Morphine did not cause a further suppression of the antibody response in beige mice compared to placebo. Because of this anomalous response to placebo treatment, the immunosuppressive effects of morphine on the antibody response/10(7) cells can not be attributed to a specific drug effect in this strain. However, when antibody responses were expressed on a per spleen basis, the overall capacity to respond to antigenic challenge was suppressed by morphine treatment.

Kinetics of allopurinol and its metabolite oxypurinol after oral administration of allopurinol alone or associated with benzbromarone in man. Simultaneous assay of hypoxanthine and xanthine by gas chromatography-mass spectrometry.

Allopurinol, oxypurinol, hypoxanthine and xanthine were assayed simultaneously using a highly specific method combining gas chromatography and mass spectrometry. Two hypo-uricaemic prescriptions were compared: i) 300 mg of allopurinol (AL); and ii) 100 mg of allopurinol plus 20 mg of benzbromarone (AL + BZB). When administered acutely, their effects on blood uric acid levels were similar. Analysis of the pharmacokinetic parameters of allopurinol and its metabolite after each treatment showed dose-linearity for the metabolite but not for the drug itself. The area under the concentration time curve for allopurinol was 40.3 +/- 9.3 mumol l-1 h after AL, against 8.4 +/- 3.9 mumol-1 h after AL + BZB, while for oxypurinol it was 948.0 +/- 125.4 mumol l-1 h after AL and 285.2 +/- 77.9 mumol l-1 h after AL + BZB. The difference in dosage form may partly account for this difference, but the benzbromarone also seems to be involved. Its role on the blood uric acid lowering action of the drug association is complex. Although benzbromarone appreciably favors the elimination of oxypurinol, which should result in a weakening of its hypo-uricaemic action, this is offset by enhanced elimination of hypoxanthine and xanthine. Renal clearance of xanthine was significantly increased under AL + BZB (173.1 +/- 65.6 ml/min against 112.2 +/- 32.9 ml/min after AL). Similarly, blood xanthine levels were proportionately higher in the presence of benzbromarone. The action of the two agents may thus be synergistic and not antagonistic, a pharmacological justification for the therapeutic use of this drug association.

Atrial septal aneurysm. Morphological characteristics in a large population: pathological associations. A French multicenter study on 259 patients investigated by transoesophageal echocardiography.

UNLABELLED: A strong association between interatrial septal aneurysm (IASA) and stroke has recently led many authors to consider IASA as a potential cardiac source of embolism. We studied the morphological characteristics and main associations of IASA in a large cooperative study based on transoesophageal echocardiographic examinations; 259 IASA were studied in 134 men and 125 women with a mean age of 59 +/- 15 years. Fifty-five percent of IASA were found to overlap the commonly described fossa ovalis region. IASA protruded into the right atrium in 90% of the cases. They appeared thin in 81% of the patients and highly mobile in 79%. Fifty-eight percent of patients had a history of systemic embolic events, while an atrial septal shunt was detected in 61% of the patients. In patients with an embolic event, only the mobility of IASA was significantly higher than in those with no embolic event. In nine cases a pulmonary embolism was associated with arterial embolism. Furthermore, we reported three cases of paradoxical embolism. However, the true demonstration of a thrombus within the IASA was quite rare. CONCLUSION: IASA is probably an important risk factor for stroke. In patients with IASA and a history of embolic events, IASA may enhance migration of a thrombus constituted in situ or transiting through it. Marked mobility of IASA may also increase the risk of peripheral embolus.

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.

XeCl excimer laser coronary angioplasty: a convergence of favourable factors.

The results of recent studies on the application of an XeCl laser to coronary angioplasty are presented. Several points are examined: the quality of the cut in human post-mortem artery, the cutting rates and threshold fluences in different media, the risks of carcinogenesis and thrombosis, and the transmission of suitable fluences in optical fibres. Recent human in vivo procedures are reported.

Immunosuppressive effects of morphine on immune responses in mice.

Implantation of a 75-mg morphine sulfate pellet subcutaneously into mice of different strains and sexes caused profound immunosuppression of their spleen cell primary in vitro antibody responses to sheep red blood cells. No sex differences were observed. In mice of the C3H lineage, naltrexone blocked the immunosuppression. In mice in the C57BL/6J lineage, naltrexone was ineffective in blocking the effects of morphine and was itself suppressive. In beige C57BL/6J bgJ/bgJ mice, placebo pellets were also suppressive. The mechanism of the morphine-induced immunosuppression was investigated in C3HeB/FeJ mice. Addition of normal splenic macrophages to in vitro cultures restored immune responses, as did IL-1, IL-6 and IFN-gamma, suggesting that morphine-induced immunosuppression is due to a deficit in macrophage function. Morphine pellet implantation induced splenic atrophy. Whether suppression is attributable to decreased macrophage numbers or to decreased functional capacity of individual macrophages is currently under investigation.

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.

Aortic occlusion in a patient with antiphospholipid antibody syndrome in systemic lupus erythematosus.

A 41-year-old woman with systemic lupus erythematosus and lupus anticoagulant developed aortic thrombosis. The patient was receiving low dose aspirin. Aortography showed a complete obliteration of the infrarenal aorta. Computed tomography and magnetic resonance imaging showed no evidence of aortitis. The patient improved with medical treatment. Six other published cases are reviewed.

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.

[Deterged large abscess of the aortic valve ring disclosed after infective endocarditis]. / Volumineux abcès détergé péri-aortique découvert à distance d'une endocardite infectieuse.

The authors report the case of a very large deterged aortic valve ring abscess detected at long-term after infective endocarditis during investigation of symptomatic consequent aortic regurgitation. The different imaging methods of diagnostic import are reviewed with special emphasis on the role of transoesophageal echocardiography during infective endocarditis.

[Exploration of left ventricular relaxation using gamma-angiography in 70 hypertensive subjects. Practical consequences and implications]. / Exploration de la relaxation ventriculaire gauche par gamma-angiographie chez soixante-dix hypertendus. Implications et conséquences pratiques.

This study was performed to evaluate the incidence ant the practical consequences of left ventricular diastolic dysfunction in hypertensive. In 70 mild to moderate hypertensive subjects group [systolic 161 +/- 16 and diastolic blood pressure 104 +/- 9 mmHg 18 women, 52 men, 51 +/- 7 years old] and in a 15 normal subjects control group, the peak filling rate (PFR) and the time to peak filling rate (TPFR) were measured with the time/activity curve of the rest equilibrium blood pool scintigraphy. The ejection fraction and the stress test were normal in all patients [EF 0.66 +/- 0.05, ranging from 0.59 to 0.88]. The PFR was not significantly different in the hypertensive group but 59/70 patients [84 p. 100] showed an individual value lower than the theoretical age and heart rate expected value. The TPFR was not significantly different (183 +/- 33 ms-vs 180, p = ns). In a Holter-defined sub-group of patients (n = 22) exhibiting a high prevalence of supra-ventricular premature beats or a paroxysmal atrial fibrillation, the PFR was significantly slower than in the total hypertensive group [1.92 +/- 0.33 EDV/s-1, p = 0.02]. Early indices of diastolic function give some instantaneous information on left ventricular filling. Determining the exact significance of individual values of PFR and TPFR requires a better knowledge of physiologic and pathologic determinants of LV filling.

[Study of left ventricular filling by gamma-angiography and echocardiography]. / Exploration du remplissage ventriculaire gauche par la gamma-angiographie et l'échocardiographie.

In order to establish which indices of early diastolic function obtained by Doppler echocardiography and the time/activity curve of 99mTc radionuclide angiography are the most useful clinically, the two investigations were performed in 41 subjects aged 52 +/- 15 years. The maximum velocity of LV filling and mitral E wave provided the best correlation (r = 0.48); the Doppler A wave did not correlate with its scintigraphic homologue. The correlations with the morphological data (mass, thickness/radius ratio) were better with radionuclide angiography. Variance analysis of E and maximum velocity of filling showed that gamma angiography was significantly more accurate (FE LVF greater than 10 p = 10 - 4); on the other hand, the A wave best illustrated the transfer of filling to late diastole. In conclusion, left ventricular filling may be assessed clinically by Doppler echocardiography; the greater accuracy of the radionuclide measurements with respect to left ventricular volumes makes this a more appropriate method when quantitative information is required.