Assessment of hand trabecular bone texture with high resolution direct digital radiograph in rheumatoid arthritis: a case control study.

OBJECTIVES: Rheumatoid arthritis is characterized by an early inflammatory related periarticular osteopenia. A new high resolution direct digital X-ray device has been recently developed to provide bone texture analysis which is designed to assess changes in trabecular bone architecture. For the first time, we have evaluated trabecular bone texture impairment in rheumatoid arthritis patients compared to healthy controls. METHODS: In this cross-sectional study, the reproducibility was assessed by three separate digital X-rays of the right hand, with repositioning in 14 late rheumatoid arthritis patients and 14 healthy subjects. Then, trabecular bone texture of the MCP2 and MCP3 from patients enrolled in a prospective cohort of 78 rheumatoid arthritis patients was compared with that of 50 healthy subjects, using three texture parameters: Hmean, co-occurrence and run-length. RESULTS: The coefficients of variation of the high resolution direct digital X-ray measurements ranged from 0.5 to 1.8%. Only the Hmean parameter was significantly decreased in rheumatoid arthritis patients compared to healthy subjects at MCP2 (0.637±0.040 vs. 0.654±0.032, P<0.05) and at MCP3 (0.646±0.044 vs. 0.665±0.037, P<0.05). This reduction was significantly correlated to disease activity. CONCLUSIONS: This study demonstrated both the good reproducibility of the high resolution digital X-ray measurements and the trabecular bone texture impairment at MCP joints in rheumatoid arthritis patients. In addition to provide a high resolution hand radiograph, this technique may represent an interesting tool to easily quantify periarticular osteopenia with a low radiation dose.

Investigation of the interface in silica-encapsulated liposomes by combining solid state NMR and first principles calculations.

In the context of nanomedicine, liposils (liposomes and silica) have a strong potential for drug storage and release schemes: such materials combine the intrinsic properties of liposome (encapsulation) and silica (increased rigidity, protective coating, pH degradability). In this work, an original approach combining solid state NMR, molecular dynamics, first principles geometry optimization, and NMR parameters calculation allows the building of a precise representation of the organic/inorganic interface in liposils. {(1)H-(29)Si}(1)H and {(1)H-(31)P}(1)H Double Cross-Polarization (CP) MAS NMR experiments were implemented in order to explore the proton chemical environments around the silica and the phospholipids, respectively. Using VASP (Vienna Ab Initio Simulation Package), DFT calculations including molecular dynamics, and geometry optimization lead to the determination of energetically favorable configurations of a DPPC (dipalmitoylphosphatidylcholine) headgroup adsorbed onto a hydroxylated silica surface that corresponds to a realistic model of an amorphous silica slab. These data combined with first principles NMR parameters calculations by GIPAW (Gauge Included Projected Augmented Wave) show that the phosphate moieties are not directly interacting with silanols. The stabilization of the interface is achieved through the presence of water molecules located in-between the head groups of the phospholipids and the silica surface forming an interfacial H-bonded water layer. A detailed study of the (31)P chemical shift anisotropy (CSA) parameters allows us to interpret the local dynamics of DPPC in liposils. Finally, the VASP/solid state NMR/GIPAW combined approach can be extended to a large variety of organic-inorganic hybrid interfaces.

Bone assessment in children with chronic kidney disease: data from two new bone imaging techniques in a single-center pilot study.

Bone damage in children with chronic kidney disease (CKD) is a challenge for pediatric nephrologists. Areal measurements of bone mineral density (BMD) by dual x-ray absorptiometry (DXA) have been routinely performed to assess bone mass but recent international guidelines have concluded that DXA was of less value in CKD. The aim of this study is to evaluate bone quality in CKD children using new bone imaging techniques in a pilot cross-sectional single-center study. We performed bone imaging (high-resolution peripheral quantitative computed tomography, HR-pQCT, XtremeCT, Scanco Medical AG, Switzerland), to assess compartmental volumetric BMD and trabecular microarchitecture in 22 CKD children and 19 controls. In seven younger patients (i.e., under 10 years of age), we performed bone texture analysis (BMA, D3A Medical Systems, France) in comparison to 15 healthy prepubertal controls. Among older children, CKD patients had significantly lower height and body weight without significant impairment of BMD and microarchitecture than healthy controls. In univariate analysis, there were significant correlations between cortical BMD and glomerular filtration rate (r= -0.46), age (r=0.60) and body mass index (r=0.67). In younger children, bone texture parameters were not different between patients and controls. Our results did not show significant differences between healthy controls and CKD children for compartmental bone densities and microarchitecture, but the small sample size and the heterogeneity of the CKD group require caution in the interpretation. Novel bone imaging techniques seem feasible in children, and further longitudinal studies are required to thoroughly explore long-term cardiovascular and bone consequences of phosphate-calcium metabolism deregulation during CKD.

Sphingolipids involvement in plant endomembrane differentiation: the BY2 case.

Sphingolipids play an essential role in the functioning of the secretory pathway in eukaryotic organisms. Their importance in the functional organization of plant cells has not been studied in any detail before. The sphingolipid synthesis inhibitor fumonisin B1 (FB1), a mycotoxin acting as a specific inhibitor of ceramide synthase, was tested for its effects on cell growth, cell polarity, cell shape, cell cycle and on the ultrastructure of BY2 cells. We used cell lines expressing different GFP-tagged markers for plant cell compartments, as well as a Golgi marker fused to the photoconvertible protein Kaede. Light and electron microscopy, combined with flow cytometry, were applied to analyse the morphodynamics and architecture of compartments of the secretory pathway. The results indicate that FB1 treatment had severe effects on cell growth and cell shape, and induced a delay in cell division processes. The cell changes were accompanied by the formation of the endoplasmic reticulum (ER)-derived tubular aggregates (FB1-induced compartments), together with an inhibition of cargo transport from the ER to the Golgi apparatus. A change in polar localization of the auxin transporter PIN1 was also observed, but endocytic processes were little affected. Electron microscopy studies confirmed that molecular FB1 targets were distinct from brefeldin A (BFA) targets. We propose that the reported effects of inhibition of ceramide biosynthesis reflect the importance of sphingolipids during cell growth and establishment of cell polarity in higher plant cells, notably through their contribution to the functional organization of the ER or its differentiation into distinct compartments.

Assessment of bone microarchitecture in chronic kidney disease: a comparison of 2D bone texture analysis and high-resolution peripheral quantitative computed tomography at the radius and tibia.

Bone microarchitecture can be studied noninvasively using high-resolution peripheral quantitative computed tomography (HR-pQCT). However, this technique is not widely available, so more simple techniques may be useful. BMA is a new 2D high-resolution digital X-ray device, allowing for bone texture analysis with a fractal parameter (H(mean)). The aims of this study were (1) to evaluate the reproducibility of BMA at two novel sites (radius and tibia) in addition to the conventional site (calcaneus), (2) to compare the results obtained with BMA at all of those sites, and (3) to study the relationship between H(mean) and trabecular microarchitecture measured with an in vivo 3D device (HR-pQCT) at the distal tibia and radius. BMA measurements were performed at three sites (calcaneus, distal tibia, and radius) in 14 healthy volunteers to measure the short-term reproducibility and in a group of 77 patients with chronic kidney disease to compare BMA results to HR-pQCT results. The coefficient of variation of H(mean) was 1.2, 2.1, and 4.7% at the calcaneus, radius, and tibia, respectively. We found significant associations between trabecular volumetric bone mineral density and microarchitectural variables measured by HR-pQCT and H(mean) at the three sites (e.g., Pearson correlation between radial trabecular number and radial H(mean) r = 0.472, P < 0.001). This study demonstrated a significant but moderate relationship between 2D bone texture and 3D trabecular microarchitecture. BMA is a new reproducible technique with few technical constraints. Thus, it may represent an interesting tool for evaluating bone structure, in association with biological parameters and DXA.

Assessment of hand bone loss in rheumatoid arthritis by high-resolution peripheral quantitative CT.

OBJECTIVES: A new high-resolution peripheral quantitative CT (HR-pQCT) system allows for in vivo assessment of bone microarchitecture and volumetric bone mineral density (vBMD) with an 82 microm isotropic resolution. With this device, the microarchitecture impairment was evaluated in patients with rheumatoid arthritis (RA) in comparison with healthy controls and measured the erosion volume at metacarpal heads (MCPs). METHODS: In this cross-sectional study, the reproducibility was first assessed by 3 HR-pQCT exams with repositioning in 14 patients with late RA and 14 healthy subjects. Then, HR-pQCT parameters were measured in a group of 93 patients with RA and 31 healthy controls. Two RA subgroups were distinguished: early RA (disease duration < or =2 years) (n=36) and late RA (n=57) and compared them to healthy controls. RESULTS: The precision of the HR-pQCT volumetric measurements as assessed with coefficient of variation ranged from 0.7% to 1.8% in patients with late RA and from 0.6% to 1.4% in healthy subjects at MCPs. Total and trabecular vBMD and trabecular thickness were significantly decreased in patients with RA compared to healthy subjects and were significantly correlated to disease activity. The erosion volume was highly correlated to a semiquantitative assessment using the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) scoring system applied to the HR-pQCT slices. CONCLUSIONS: This study demonstrated the good reproducibility of the HR-pQCT volumetric measurements at MCPs and confirmed the involvement of trabecular compartment in periarticular osteopoenia. Thus, HR-pQCT appears interesting to simultaneously assess differences in bone volumetric density, microarchitecture and erosions.

A comparative review of the different techniques to assess hand bone damage in rheumatoid arthritis.

Inflammatory related hand bone damage in rheumatoid arthritis is characterized by erosions and periarticular osteoporosis and can lead to substantial clinical disability. So far, conventional radiograph has been considered to be the gold standard for detecting bone damage and monitoring disease progression, but it lacks sensitivity. So other techniques have been recently developed to identify erosions earlier, to be able to change therapy; if necessary. This report reviews, in its first part, the different ways of detecting erosions such as conventional radiograph, magnetic resonance imaging or imaging ultrasonography and, in its second part, the techniques used for the assessment of hand periarticular osteoporosis like dual-X-ray absorptiometry, digital-X-ray radiogrammetry or quantitative ultrasonography.

Serious infections in patients with ankylosing spondylitis with and without TNF blockers: a systematic review and meta-analysis of randomised placebo-controlled trials.

BACKGROUND: Tumour necrosis factor (TNF) blockers are known to increase the risk of serious infections in rheumatoid arthritis. Despite wide use of TNF blockers in ankylosing spondylitis (AS), the infection risk has never been evaluated in this disease. OBJECTIVES: To assess serious infections in patients with AS not exposed and exposed to TNF blockers. METHODS: A systematic literature review up to May 2008 using PubMed, EMBASE and Cochrane Library was performed. All randomised controlled trials (RCTs) published between 1995 and 2008 monitoring serious infections, treated with non-steroidal anti-inflammatory drugs (NSAIDs) or TNF blockers, were included. Infection risks were calculated by naive pooling and for 100 patient-years (pyrs) of exposure. To assess the serious infection risk with TNF blockers, a meta-analysis of RCTs was performed using Mantel-Haenszel's method with several sensitivity analyses. RESULTS: Fourteen RCTs were included (3345 patients). With placebo or NSAIDs (N=2202), two serious infections were observed (0.09%, range 0.01% to 0.3%)-that is, 0.4/100 pyrs. In TNF blocker trials, two serious infections were observed with placebo (2/500, 0.4% (0.0% to 1.4%), ie, 1.0/100 pyrs) versus 14 serious infections with TNF blockers (14/996, 0.7% (0.3% to 1.4%), ie, 1.9/100 pyrs). Meta-analysis of the RCTs showed that the increase in serious infections with TNF blockers compared with placebo was not significant: risk difference=0.4% (-0.8% [corrected] to 1.6%). CONCLUSIONS: The absolute risk of serious infections in patients with AS not exposed to TNF blockers is low. The absolute risk of serious infections in patients receiving TNF blockers is higher, but the difference was found to be not significant, possibly through lack of power. Continued monitoring is necessary.

Influence of RANKL inhibition on immune system in the treatment of bone diseases.

Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for osteoclast differentiation, activation and survival. Recently, denosumab, a human monoclonal antibody to RANKL, has been tested in the treatment of osteoporosis. But the interactions between RANKL, receptor activator of nuclear factor-kappaB (RANK) and osteoprotegerin (OPG) are also involved in immune regulations in addition to bone metabolism. So, blocking RANKL could interplay with immune cells and have systemic effects. Here, we review biological data regarding potential consequences of RANKL blocking on the immune system.

Prevalence of substance use in a Swiss psychiatric hospital: interview reports and urine screening.

BACKGROUND: Co-morbid substance misuse is common in psychiatric disorders, has potentially severe adverse consequences and may be frequently undetected. AIMS: To measure the prevalence of substance use among patients admitted to a Swiss psychiatric hospital and to examine the potential utility of routine urine drug screening in this setting. METHOD: 266 inpatients were included. 238 patients completed the interview and 240 underwent a urine drug screening. RESULTS: Lifetime prevalence of substance use among psychiatric patients was very high for alcohol (98%; 95% CI: 96-100), benzodiazepines (86%; 95% CI: 82-91) and cannabis (53%; 95% CI: 47-60), but also for "hard drugs" like cocaine (25% ; 95% CI: 19-30) or opiates (20%; 95% CI: 15-25). Regular current use of alcohol (32%; 95% CI: 26-38) or cannabis (17%; 95% CI: 12-22) was the most frequent. Substance use was associated with male sex, younger age, unmarried status and nicotine smoking. Urine screening confirms reports from patients on recent use, and remained positive for cannabis during hospitalisation, but not for cocaine nor for opiates. CONCLUSION: Substance use is frequent among psychiatric patients. Systematic interviewing of patients about their substance use remains essential, and is usually confirmed by urine screening. Urine screening can be useful to provide specific answers about recent use.

Quantitative aspects of the spatial distribution and morphological characteristics of the sea bass (Dicentrarchus labrax L.; Teleostei, Serranidae) trunk lateral line neuromasts.

The results presented herein report quantitative data relative to the distribution and morphological characteristics of both types of neuromasts encountered on the trunk lateral line of the sea bass (Dicentrarchus labrax, L.). These data were obtained from scanning electron micrographs. They indicate that, as expected, each modified scale of the sea bass possessed a single canal neuromast with long axis oriented parallel to the fish's long axis. In contrast to several fish species, two thirds of superficial neuromasts observed herein were oriented perpendicular to the fish's long axis. However, whatever the main orientation of superficial neuromasts, two thirds of their hair bundles were oriented parallel to the long axis of the animal with approximately half of them in the direction of the head. Similar ratios were observed for canal neuromasts whatever the area of the maculae: central or peripheral. For both types of neuromasts it was not possible to clearly distinguish a paired organization of hair bundles with opposing polarities. Superficial neuromasts on each trunk canal scale were located on either the dorsal or ventral side of the canal and appeared to be distributed along the trunk lateral line with a higher probability to be encountered closer to the operculum. The frequency of presence and the average number of superficial neuromasts per scale increased with fish size. We observed a size gradient for canal neuromasts between the operculum and caudal peduncle. This gradation was correlated with a reduction of the width of the central area of the canal segment. Canal neuromasts were always localized in the larger portions of the canal segments. Taken together, these results point out some specific features associated with the sea bass trunk lateral line. With the previous report, they establish the first full description of the trunk lateral line of sea bass and will be useful for upcoming experiments regarding the function of the two types of neuromasts.

Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity.

OBJECTIVE: We investigated whether the oral administration of a low dose (75 micro g) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. METHODS: Plasma concentrations of midazolam, 1'OH-midazolam and 4'OH-midazolam were measured after the oral administration of 7.5 mg and 75 micro g midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2 days with ketoconazole (200 mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4 days with rifampicin (450 mg q.d.), a CYP3A inducer. RESULTS: After oral administration of 75 micro g midazolam, the 30-min total (unconjugated + conjugated) 1'OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean+/-SD): 6.23+/-2.61, 0.79+/-0.39 and 56.1+/-12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1'OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r(2)=0.64, P<0.001) and in the three groups taken together (r(2)=0.91, P<0.0001). Good correlations were also observed between midazolam plasma levels and midazolam clearance, measured between 1.5 h and 4 h. CONCLUSION: A low oral dose of midazolam can be used to phenotype CYP3A, either by the determination of total 1'OH-midazolam/midazolam ratios at 30 min or by the determination of midazolam plasma levels between 1.5 h and 4 h after its administration.

Pharmacokinetics of midazolam in CYP3A4- and CYP3A5-genotyped subjects.

OBJECTIVE: We investigated whether differences in pharmacokinetics of midazolam, a CYP3A probe, could be demonstrated between subjects with different CYP3A4 and CYP3A5 genotypes. METHODS: Plasma concentrations of midazolam, and of total (conjugated + unconjugated) 1'OH-midazolam, and 4'OH-midazolam were measured after the oral administration of 7.5 mg or of 75 micro g of midazolam in 21 healthy subjects. RESULTS: CYP3A5*7, CYP3A4*1E, CYP3A4*2, CYP3A4*4, CYP3A4*5, CYP3A4*6, CYP3A4*8, CYP3A4*11, CYP3A4*12, CYP3A4*13, CYP3A4*17 and CYP3A4*18 alleles were not identified in the 21 subjects. CYP3A5*3, CYP3A5*6, CYP3A4*1B and CYP3A4*1F alleles were identified in 20, 1, 4 and 2 subjects, respectively. No statistically significant differences were observed for the AUC(inf) values between the different genotypes after the 75- micro g or the 7.5-mg dose. CONCLUSION: Presently, CYP3A4 and CYP3A5 genotyping methods do not sufficiently reflect the inter-individual variability of CYP3A activity.

Spatial distribution and morphological characteristics of the trunk lateral line neuromasts of the sea bass (Dicentrarchus labrax, L.; Teleostei, Serranidae).

The morphology and spatial distribution of the different types of neuromasts encountered on the trunk lateral line of the sea bass (Dicentrarchus labrax) were examined using scanning electron microscopy. The sea bass trunk lateral line exhibits a complete straight pattern. In their basic features, the two types of neuromasts present, canal and superficial, resemble what has been described in other fishes. They are similar in their general cellular organization but differ in sizes, and shapes, as well as in the densities and lengths of their hair bundles. However, the sea bass trunk lateral line distinguishes itself in several ways. For instance, the pores of the canal segments are partially obstructed due to the overlap of scales throughout the trunk. Moreover, based on the density and length of the hair bundles, two distinct areas, central and peripheral, could be distinguished within the maculae of canal neuromasts. Their cupulae are also peculiar as they possess two wing-like extensions and that their central core appears to be organized in layers instead of columns. In addition, the superficial neuromasts, up to 6 per scale, are either round or elliptical and seem to be distributed serendipitously. Finally, within the maculae of both types of neuromasts, a significant number of hair bundles do not follow the two-directional polarity pattern usually described. Although some hypotheses are proposed, the influence of these characteristics in terms of signal encoding and fish behavior is yet to be understood.

Regional analysis of whole cell currents from hair cells of the turtle posterior crista.

The turtle posterior crista is made up of two hemicristae, each consisting of a central zone containing type I and type II hair cells and a surrounding peripheral zone containing only type II hair cells and extending from the planum semilunatum to the nonsensory torus. Afferents from various regions of a hemicrista differ in their discharge properties. To see if afferent diversity is related to the basolateral currents of the hair cells innervated, we selectively harvested type I and II hair cells from the central zone and type II hair cells from two parts of the peripheral zone, one near the planum and the other near the torus. Voltage-dependent currents were studied with the whole cell, ruptured-patch method and characterized in voltage-clamp mode. We found regional differences in both outwardly and inwardly rectifying voltage-sensitive currents. As in birds and mammals, type I hair cells have a distinctive outwardly rectifying current (I(K,L)), which begins activating at more hyperpolarized voltages than do the outward currents of type II hair cells. Activation of I(K,L) is slow and sigmoidal. Maximal outward conductances are large. Outward currents in type II cells vary in their activation kinetics. Cells with fast kinetics are associated with small conductances and with partial inactivation during 200-ms depolarizing voltage steps. Almost all type II cells in the peripheral zone and many in the central zone have fast kinetics. Some type II cells in the central zone have large outward currents with slow kinetics and little inactivation. Although these currents resemble I(K,L), they can be distinguished from the latter both electrophysiologically and pharmacologically. There are two varieties of inwardly rectifying currents in type II hair cells: activation of I(K1) is rapid and monoexponential, whereas that of I(h) is slow and sigmoidal. Many type II cells either have both inward currents or only have I(K1); very few cells only have I(h). Inward currents are less conspicuous in type I cells. Type II cells near the torus have smaller outwardly rectifying currents and larger inwardly rectifying currents than those near the planum, but the differences are too small to account for variations in discharge properties of bouton afferents innervating the two regions of the peripheral zone. The large outward conductances seen in central cells, by lowering impedances, may contribute to the low rotational gains of some central-zone afferents.