Antibody- and macrophage-mediated segmental demyelination in chronic inflammatory demyelinating polyneuropathy: clinical, electrophysiological, immunological and pathological correlates.

BACKGROUND AND PURPOSE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous autoimmune disorder critically lacking diagnostic biomarkers. Autoantibodies to nodal and paranodal components have recently been described in a small subset of patients. Here, the diagnostic value of immune reactivity toward the myelin compartment was investigated. METHODS: Ninety-four French CIDP patients were retrospectively studied. The reactivity toward the peripheral nerve was investigated. Sural nerve biopsies were examined by electron microscopy and immunofluorescence. RESULTS: Twenty-one patients (22%) and three patients (3%) presented with a strong immunoglobulin G or immunoglobulin M reactivity respectively against the myelin compartment. The clinical, electrophysiological and morphological features were examined in nine of these patients for whom sural nerve biopsies were available. Seven patients were electrodiagnosed with definite CIDP, one with possible CIDP and one was unclassifiable but sural nerve biopsy argued for CIDP diagnosis. Electron microscopy of sural nerve biopsies demonstrated the presence of macrophage-mediated demyelination restricted to the internode in all nine patients. Immunolabelling for voltage-gated sodium channels, myelin and axonal markers confirmed the presence of segmental demyelination and of remyelination. The nodal and paranodal regions, however, were unaffected in these patients. Nerve conduction studies corroborated the multifocal and segmental profile, and seven patients showed increased duration of proximal (1.5-5.1 times) and/or distal (1.2-3.4 times) compound muscle action potential in at least two nerves. CONCLUSION: Antibody- and macrophage-mediated demyelination appears responsible for conduction alterations in CIDP patients and nerve immunostaining assays may serve as a supportive diagnostic biomarker.

[New insights on the organization of the nodes of Ranvier]. / Nouveautés sur les mécanismes de formation des nœuds de Ranvier.

Myelin plays a crucial role in the rapid and saltatory conduction of the nerve impulse along myelinated axons. In addition, myelin closely regulates the organization of the axonal compartments. This organization involves several complex mechanisms including axo-glial contact, diffusion barriers, the cytoskeletal network, and the extracellular matrix. In peripheral nerves, the axo-glial contact dictates the formation of the nodes and the clustering of the voltage-gated sodium channels (Nav). The axo-glial contact at nodes implicates adhesion molecules expressed by the Schwann cell (gliomedin and NrCAM), which binds a partner, neurofascin-186, on the axonal side. This complex is essential for the recruitment of ankyrin-G, a cytoskeletal scaffolding protein, which binds and concentrates Nav channels at nodes. The paranodal junctions flanking the nodes also play a complementary function in node formation. These junctions are formed by the association of contactin-1/caspr-1/neurofascin-155 and create a diffusion barrier, which traps proteins at the nodes and dampens their diffusion along the internode. In the central nervous system, the mechanisms of node formation are different and the formation of the paranodal junctions precedes the aggregation of Nav channels at nodes. However, node formation can still happen in absence of paranodal junctions in the CNS. One explanation is that NF186 interacts with components of the extracellular matrix around the node and thereby stabilizes the aggregation of nodal proteins. It is likely that many other proteins are also implicated in the signaling pathways that regulate the differentiation of the axonal compartments. The nature and function of these proteins are yet to be identified.

Investigating filler morphology and mechanical properties of new low-shrinkage resin composite types.

Three types of low-shrinkage composites are today commercially available: Ormocers, cationic ring-opening curing systems and highly filled methacrylate-based materials, which cure via free-radical polymerization mechanisms. The aim of this study was to characterize the inorganic fraction of materials belonging to each type and to compare their mechanical properties. Two Ormocers (Admira and an experimental Ormocer V35694), one ring-opening composite (Filtek Silorane) and five methacrylate-based composites [Filtek Supreme XT, Tetric EvoCeram, Grandio, Synergy D6 (Coltène-Whaledent, Langenau, Germany) and an experimental material, V34930] were tested. Inorganic fillers were quantified by thermogravimetric analysis and morphologically characterized by scanning electron microscopy. Dynamic modulus was determined by an impulse excitation technique, static elastic moduli and flexural strength by a three-point bending method. The results were analyzed using ANOVA tests (P < 0.05) and linear correlations. Grandio, V34930 and V35694 exhibited significantly higher filler mass fractions. Both dynamic and static moduli of Grandio and V34930 were significantly higher than the other materials (P < 0.05), although no significant difference in flexural strength was observed between material type (P > 0.05). From the present findings, it was suggested that V35694 and Filtek Silorane exhibit comparable properties to conventional methacrylate-based composites, although clinically the cavity type and location must guide material choice. Under high occlusal load, the use of Grandio and V34930 might be favoured. For small cavities, alternative technologies could be preferred as the need for mechanical resistance is lower and the potential for stress generation is greater.

Thyrotropin variations may explain some positive radioiodine therapy scans in patients with negative diagnostic scans.

UNLABELLED: Thyroglobulin (Tg) is a specific marker of residual thyroid cancer or tumor recurrence. In patients with elevated Tg levels and negative diagnostic radioiodine (131I) whole-body scans (dWBS), administration of a therapy dose may reveal foci that were not initially apparent. The aim of this study was to identify factors, other than 131I activity, which might explain why a post-therapy 131I whole-body scan is sometimes positive despite a negative dWBS. PATIENTS AND METHODS: We reviewed data on all patients with elevated Tg levels and negative dWBS with 185 MBq 131I off-T4 at followup, who subsequently received an empiric therapy dose of 3700 MBq of 131I. During a 5-yr period, 22 patients met these criteria. 131I therapy could be given immediately after negative dWBS in 9 patients, with an average of 8 extra days of hypothyroidism. In the other 13 patients, therapy was given an average of 8 months later. RESULTS: The therapy scan was negative in 16 patients, while it showed uptake in the thyroid bed in 5 patients and distant metastases in two. In the latter two patients, the TSH level was suboptimal at the time of dWBS (9 and 25 microIU/ml), and had risen to 34 and 70 microIU/ml respectively at the time of therapy. Overall, a positive scan following therapy occurred in 7 patients (6/9 patients treated immediately and 1/13 patients treated in a separate setting; p<0.01). In patients with positive therapy scans, the mean TSH level was 73 microIU/ml at the time of dWBS and 103.5 microIU/ml at the time of therapy (41% increase; p<0.05). In patients with negative therapy scans the mean TSH level was 84 microIU/ml at dWBS and 86 microIU/ml at the time of the therapy scan (2% increase). CONCLUSIONS: Our study suggests that interval increase in TSH level with a longer period of stimulation may have contributed to making the whole-body scan positive at the time of therapy. Nowadays, patients with elevated Tg are directly given a therapy dose of 131I. Special care should be taken when preparing patients who have been on suppressive levothyroxine therapy for a long time, in order to avoid misclassifying the tumor as non-functioning.

[Early detection of myocardial disease in young patients with Becker's muscular dystrophy asymptomatic from the cardiac point of view: value of myocardial doppler tissue imaging]. / Detection précoce de l'atteinte myocardique chez des jeunes patients atteints de dystrophie musculaire de Becker asymptomatique sur le plan cardiaque Intérêt du doppler tissulaire myocardique.

Becker's muscular dystrophy is an X-linked hereditary disorder characterised by progressive muscle weakness and possible cardiac disease. Cardiac involvement is assumed to be rare in young patients. Early diagnosis could lead to earlier treatment at an infra-clinical stage of the disease. The object of the study was to evaluate systolic and diastolic cardiac function of young patients with Becker's disease by echocardiography and using Doppler tissue imaging. Consecutive patients under 20 years of age with Becker's disease confirmed genetically were included and compared with paired normal subjects. Subendocardial and subepicardial myocardial velocities were obtained by Doppler tissue imaging and the corresponding velocity gradients were measured. Twelve patients were included (17.4 +/- 2.5 years). None of them had disabling muscle disease. No significant difference was observed from normal subjects with respect to: ventricular dimensions, wall thickness, fractional shortening, E/A ratio measured by transmitral Doppler. Nevertheless, patients with Becker's disease had lower systolic and diastolic intra-myocardial velocity gradients: 2.2 +/- 1.1 vs. 4.7 +/- 2.4 s(-1), p = 0.006, and 3.6 +/- 2.0 vs. 5.6 +/- 1.3 s(-1), p = 0.048, respectively, compared with the control group. These results show that myocardial disease is possible in patients with Becker's muscular dystrophy under the age of 20. Myocardial Doppler tissue imaging is a sensitive method for detecting these early abnormalities and should be recommended in the young patients.

Coupling of the biochemical composition and calorific content of zooplankters with the Microcystis aeruginosa proliferation in a highly eutrophic reservoir.

The impact of the Cyanobacteria Microcystis aeruginosa on zooplankton dynamics was studied in the hypertrophic Villerest Reservoir (France). Samples were collected and their biochemical composition and calorific content examined. Three most abundant zooplankton species in the reservoir were considered: the cladoceran Daphnia longispina and the copepods Cyclops vicinus and Eudiaptomus gracilis. The three species were differently affected by the Microcystis aeruginosa blooms. Daphnia longispina did not seem to suffer from the proliferation of the M. acruginosa, although its biomass decreased concomitantly to the bloom. This collapse would be attributable to the lack of nutritional value of algae. Cyclops vicinus seemed to move away when Microcystis invaded the superficial layers of the reservoir. Because this zooplankter had migratory abilities, it reached the littoral zone where food was available. The energetic costs linked to this migration were clearly pointed out when the species recovered the pelagial zone in early fall. The behaviour of Eudiaptomus gracilis was not clear. This species underwent diapause as M. aeruginosa proliferated. This suggests that Eudiaptomnus gracilis moved away from the pelagial zone over the cyanobacterial blooms. In most cases, the cyanobacterial toxins affected the growth of zooplankton and the potential to use herbivorous zooplankton as a means to combat Microcystis proliferation in the Villerest reservoir seems limited.

[Familial small-vessel vasculitis of the kidney]. / Vascularite familiale des vaisseaux de petit calibre des reins.

INTRODUCTION: Familial forms of small-vessel vasculitis has been reported in 14 families (including this one). CASES: A father and son were both diagnosed with renal vasculitis (pauci-immune crescentic glomerulonephritis). Both had antimyeloperoxidase autoantibodies, and there was no evidence of a common environmental factor. DISCUSSION: These cases suggest the role of constitutional factors in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis.

The effect of captopril on thallium 201 myocardial perfusion in systemic sclerosis.

In systemic sclerosis, abnormalities of myocardial perfusion are common and may be caused by a disturbance of the coronary microcirculation. We evaluated the long-term effect of captopril (75 to 150 mg per day) on thallium 201 myocardial perfusion in 12 normotensive patients with systemic sclerosis. Captopril significantly decreased the mean (+/- SD) number of segments with thallium 201 myocardial perfusion defects (6.5 +/- 1.9 at baseline and 4.4 +/- 2.7 after 1 year of treatment with captopril; p less than 0.02) and increased the mean global thallium score (9.6 +/- 1.7 at baseline and 11.4 +/- 2.1 after captopril; p less than 0.05). In a control group of eight normotensive patients with systemic sclerosis who did not receive captopril, no significant modification in thallium results occurred. Side effects with captopril included hypotension (six patients), taste disturbances (one patient), and skin rash (one patient). These side effects subsided when the dosage was reduced. These findings demonstrate that captopril improves thallium 201 myocardial perfusion in patients with systemic sclerosis and may therefore have a beneficial effect on scleroderma myocardial disease.

Non-invasive evaluation of the cardiac function in golden retriever dogs by radionuclide angiography.

Golden Retriever dogs manifest an X-linked, Duchenne-like, muscular dystrophy with a characteristic lack of dystrophin. Histologic findings have demonstrated the cardiac involvement in these dogs to be a model for the cardiac insufficiency in human Duchenne muscular dystrophy (DMD). The goal of this study was to assess the capability of radionuclide angiography (RNA) as an assessment tool to measure the ventricular dysfunction in these dogs. Three dogs, one normal and two with muscular dystrophy (MD), were studied by equilibrium gated blood pool. Red blood cells were labelled with 420 MBq of 99mTc. The three dogs lying on their left sides on the table, received no drugs and were not restrained in any manner. RNA left ejection fraction (EF) and echographic measurements of left ventricular fractional shortening (FS) were performed during the same session. EF values were 61%, 48%, 36% and FS values were 47%, 32%, 26%, respectively, for the control dog, the 6 month old MD dog and the 12 month old MD dog. This preliminary study demonstrates the potential usefulness of RNA for the non-invasive follow-up exams of specific therapy in a canine model of muscular dystrophy.

Role of tricuspid regurgitation and left ventricular damage in the treatment of right ventricular infarction-induced low cardiac output syndrome.

To evaluate, in right ventricular (RV) myocardial infarction, the role of tricuspid regurgitation (TR) and left ventricular (LV) damage and the response to treatment of low cardiac output, 20 patients were prospectively studied. Volume infusion increased cardiac output only slightly (11%, p less than 0.001), despite a dramatic increase in ventricular filling pressures. Dobutamine (4 micrograms.kg-1.min-1) markedly increased cardiac output (24%, p less than 0.001) with a decrease in ventricular filling pressures. In the 5 patients with TR, dobutamine only modestly increased cardiac output (9 vs 26%, p less than 0.001), while stroke index and LV end-diastolic dimensions decreased in comparison (-5 vs 33% and -6 vs 9%, respectively, p less than 0.001). In the absence of TR (n = 15), there was no significant difference in response to volume expansion between patients with normal (n = 7) and depressed LV ejection fraction (n = 8). In contrast, dobutamine, in patients with depressed LV function, induced a greater increase in cardiac output (38 vs 17%, p less than 0.01) and RV ejection fraction (36 vs 12%, p less than 0.05). All patients with RV infarction-induced low cardiac output responded only modestly to volume loading. Dobutamine is particularly efficacious in patients without TR who have depressed LV function by improving RV function and, consequently, LV preload. In the 5 patients with TR, increasing RV contractility failed to improve the forward stroke volume by increasing the regurgitant fraction.

Mechanisms of decreased left ventricular preload during continuous positive pressure ventilation in ARDS.

Continuous positive pressure ventilation is associated with a reduction in left ventricular preload and cardiac output, but the mechanisms responsible are controversial. The decrease in left ventricular preload may result exclusively from a decreased systemic venous return due to increased pleural pressure, or from an additional effect such as decreased left ventricular compliance. To determine the mechanisms responsible, we studied the changes in cardiac output induced by continuous positive pressure ventilation in eight patients with the adult respiratory distress syndrome. We measured cardiac output by thermodilution, and biventricular ejection fraction by equilibrium gated blood pool scintigraphy. Biventricular end-diastolic volumes were then calculated by dividing stroke volume by ejection fraction. As positive end-expiratory pressure increased from 0 to 20 cm H2O, stroke volume and biventricular end-diastolic volumes fell about 25 percent, and biventricular ejection fraction remained unchanged. At 20 cm H2O positive end-expiratory pressure, volume expansion for normalizing cardiac output restored biventricular end-diastolic volumes without markedly changing biventricular end-diastolic transmural pressures. The primary cause of the reduction in left ventricular preload with continuous positive pressure ventilation appears to be a fall in venous return and hence in right ventricular stroke volume, without evidence of change in left ventricular diastolic compliance.

Right ventricular performance in patients with acute respiratory failure.

To examine the right ventricular response to acute respiratory failure, serial studies of biventricular performance were analysed in 34 such patients, specifically detailing the role of associated underlying disease. During the initial study, the 34 patients with acute respiratory failure had a higher right ventricular end-diastolic volume than the control group (+21%), associated with a decrease in right ventricular ejection fraction, abnormalities which tended to return to normal values in the 15 survivors. In the 9 patients who died of refractory hypoxemia with severe pulmonary hypertension, the right ventricular dilation allowed to maintain stroke volume. In contrast, in 8 patients who died of septic shock, biventricular function was progressively altered (right and left ventricular ejection fraction = -37% and -35%). In 4 patients who died of cardiogenic shock (viral myocarditis), the cardiac function was the lowest (right and left ventricular ejection fraction = -59% and -60%). Only patients with acute respiratory failure associated with septic shock or viral myocarditis are unable to maintain their stroke volume.

The Microbial Food Web in the Recently Flooded Sep Reservoir: Diel Fluctuations in Bacterial Biomass and Metabolic Activity in Relation to Phytoplankton and Flagellate Grazers.

The spatial distribution of the bacterial biomass and production and of potential heterotrophic activity (PHA) were measured every 4 h between 23 July (10:00 h) and 25 July (10:00 h) 1997 in a recently flooded oligo-mesotrophic reservoir (the Sep Reservoir, Puy-de-Dôme, France), in relation to temperature, the phytoplankton biomass and production, and the abundance of heterotrophic flagellates. The temperature varied slightly with time during the study, but the well-established thermal stratification agreed well with vertical distribution of the biological variables that were measured. Only the bacterial production and the PHA showed significant diel changes (t-test, p <0.05), with maxima at 18:00 h and minima at 02:00 h. A significant positive relation was found between bacterial abundance and that of heterotrophic flagellates, which, rather than being an association related to the thermal stratification of the water column, was considered to reflect a trophic relation between these two communities. A carbon balance analysis suggested that at least 30% of the C from primary production measured during the sampling period was used by bacteria, and that 42% of this secondary production, or 6% of the primary production, would be used for the development of the heterotrophic flagellates present. We conclude that the bacterioplankton forms, at least occasionally, an important source of carbon for higher trophic levels, and reject the hypothesis that bacterial production in the Sep Reservoir depends exclusively on organic matter of allochthonous origin.

Better results with rhenium-186 radiosynoviorthesis than with cortivazol in rheumatoid arthritis (RA): a two-year follow-up randomized controlled multicentre study.

OBJECTIVE: The aim of this international multicentric randomized phase 3 clinical trial was to compare prospectively radiosynoviorthesis (RSO) with rhenium-186-sulfide (186Re) to intra-articular corticotherapy in patients with clinically controlled rheumatoid arthritis (RA), but in whom one or a few medium-sized joints remained painful or swollen. METHODS: One hundred and twenty-nine joints in 81 RA patients [stratified into 2 groups: wrists (group 1, n = 78) and all the other joints (group 2, n = 51, including 18 elbows, 21 shoulders and 12 ankles)] were randomized to receive intra-articular injections of either 186Re-sulfide (64 +/- 4 MBq), or cortivazol (Altim) 3.75 mg. Clinical assessment was performed before and then at 3, 6, 12, 18 and 24 months after local therapy, using a 4-step verbal rating scale (VRS) and a 100 mm visual analog scale for pain, a 4-step VRS for joint swelling and mobility and a 2-step VRS for the radiological stage. The Mantel-Haenszel test was used for qualitative variables, analysis of variance (ANOVA) for quantitative pain analysis and Kaplan-Meyer survival test for relapse analysis. RESULTS: 186Re was observed to be statistically superior to cortivazol at 18 and 24 months while no statistical difference was seen for any criterion at 3, 6 and 12 months post injection. At 24 months, the difference in favor of 186Re was significant for pain (p = 0.024), joint swelling (p = 0.01), mobility (p = 0.05, non-wrists only), pain and swelling (p = 0.03) and pain or swelling (p = 0.02). "Survival" studies (Kaplan-Meyer) demonstrated a greater relative risk of relapse in corticoid treated joints, but only from the second year of follow-up. No serious side effect was observed in any patient, with only light and transient local pain and/or swelling occurring in 24% of cases, regardless of the treatment used. CONCLUSION: 186Re-sulfide and cortivazol had similar efficacy up to 12 months post-injection, but 186Re became clearly more effective at 18 and 24 months, for all criteria monitored and for RA outcome. Therefore, 186Re RSO can be recommended for routine clinical use.

169Erbium-citrate synoviorthesis after failure of local corticosteroid injections to treat rheumatoid arthritis-affected finger joints.

OBJECTIVES: Intra-articular injection of 169Erbium-citrate (169Er-citrate; radiosynoviorthesis or radiosynovectomy) is an effective local treatment of rheumatic joint diseases. However, its efficacy in corticosteroid-resistant rheumatoid arthritis-affected joints has not been clearly demonstrated. METHODS: A double-blind, randomised, placebo-controlled, international multicentre study was conducted in patients with rheumatoid arthritis with recent (< or = 24 months) ineffective corticosteroid injection(s) into their finger joint(s). Eighty-five finger joints of 44 patients were randomised to receive a single injection of placebo (NaCl 0.9%) or 169Er-citrate. Results of evaluation 6 months later were available for 82 joints (46 metacarpophalangeal and 36 proximal interphalangeal joints) of 42 patients: 39 169Er-citrate-injected joints and 43 placebo-injected joints. Efficacy was assessed using a rating scale for joint pain, swelling and mobility. RESULTS: Intent-to-treat analysis of the results of the 82 joints showed a significant effect of 169Er-citrate compared to placebo for the principal criteria decreased pain or swelling (95 vs 79%; p = 0.038) and decreased pain and swelling (79 vs 47%; p = 0.0024) and for the secondary criteria decreased pain (92 vs 72%; p = 0.017), decreased swelling (82 vs 53%; p = 0.0065) and increased mobility (64 vs 42%; p = 0.036). Per-protocol analysis, excluding 18 joints of patients who markedly changed their usual systemic treatment for arthritis, gave similar percentages of improvement but statistical significance was lower owing the reduced power of the statistical tests. CONCLUSION: These results confirm the clinical efficacy of 169Er-citrate synoviorthesis of rheumatoid arthritis-diseased finger joints after recent failure of intra-articular corticotherapy.

Color quantitation through image processing in dermatology.

Classical color models and their applications to computer vision are reviewed. The performances of color quantitation from digitized images are compared with those derived from a chromameter. The color quantitation obtained from either digitized color slides or directly digitized images is proved to be more efficient than the conventional visual assessment of observers. A methodology is proposed for determining the specific color indices which are needed in dermatology. An application of this methodology is developed for designing a blanching quantitation index in order to replace the visual assessment during McKenzie tests.

An automated system for the registration and comparison of photographic images in medicine.

A system is presented for digitization and automated comparison of photographic images of patients obtained at different times using a high-precision video camera. The images can be acquired either directly or from slides. The two images to be compared are registered using a complex geometrical and gray-level registration model including six parameters (planar, translation, rotation, magnification, linear transformation of the gray levels). The values of the registration parameters are automatically calculated by maximizing an integer similarity measure selected for robustness. The optimization of this function with respect to the registration parameters is performed using an adaptive random search strategy. The analysis of the differences between the registered images can be carried out through visual inspection of the subtraction image in which artifacts due to remaining infrapixel shifts have been suppressed.

Evidence for the contribution of ciliates to denitrification in a eutrophic lake.

High levels of nitrate reductase (NR) activity were found during a field survey in the epilimnion and metalimnion of a temperate lake (Lake Aydat, France) during summer stratification, when nitrates were analytically undetectable (< 0.5 mg L(-1)). We hypothesized that the NR activities were due to phytoplankton in the epilimnion, due to the ciliate Loxodes at the mid-depth oxic/anoxic interface and preferentially due to bacteria in the anoxic hypolimnion of the lake. In support of the hypothesis, a significant negative correlation was detected in the metalimnion between the abundance of Loxodes and nitrate concentrations, indicating nitrate use by the ciliate, and significant positive correlations were found between bacteria and nitrite concentrations at depth. The correlations are corroborated by additional evidence from chlorophyll a/NRA ratios, nitrite dynamics, and lake circulation patterns. Other ciliates besides Loxodes did not appear to significantly contribute to NRA potential. The data suggest that facultatively anaerobic ciliates such as Loxodes may be significant contributors to denitrification in eutrophic planktonic ecosystems.

Usefulness of simultaneous use of several methods for the estimation of phytoplanktonic biomass.

The annual cycle of phytoplankton biomass was followed in a eutrophic lake (Lake Aydat, Massif Central, France), using classic descriptors (biovolumes and chlorophyll a) as well as adenosine-5'-phosphate (ATP) levels. ATP is the metabolite indicating living biomass. ATP/Cell count and ATP/Chlorophyll a ratios were elevated due to the presence of heterotrophic organisms, such as several species of ciliates. The first ratio is greater than the second. The difference can be explained either by an underestimation of the nanoplankton fraction through the cell count method, or by a lack of sedimentation in the settling chambers used for counting cells.