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Hyaluronic acid (HA) has a high affinity for the CD44 receptor present at the surface of articular cells, particularly of chondrocytes. HA-covered polylactide nanoparticles containing bioactive compounds such as HA and chondroitin sulfate (CS) were thus prepared in order to achieve a controlled delivery targeted to cartilage cells after injection near articular alterations/erosions. Such nanoparticles (diameter = 700 nm) were prepared by double emulsion/solvent evaporation, using amphiphilic derivatives of HA, as stabilizer of the secondary emulsion. These nanoparticles were incubated with articular cells, and several tests were carried out. First, they proved that the nanospheres provoked no decrease in cell viability, even after 72 h of contact. Second, a confocal microscopy analysis on fluorescent HA-covered particles showed that they were captured by articular cells, while with those covered with poly(vinyl alcohol), the uptake was far lower. Third, a scattering electron microscopy analysis proved that the HA-coated nanoparticles were localized in the cell intracytoplasmic area.

Despite that on clinical systems phased array technology is now widely used, the high field MRI experimental systems with multiple receiver channels just became available few years ago. For this reason and due to the large range of magnetic field (frequencies between 200 and 500 MHz for proton resonance), commercial phased arrays implemented in narrow bore for high field applications are rare and relatively expensive. Array coil imaging is an advanced method for acquiring high resolution images with enhanced signal-to-noise ratio (SNR) and/or enlarged field of view (FOV) compared for example to single loop surface coil. The volume of interest is then covered by several coil elements and images reconstructed for every single channel are combined afterwards. The goal of this work was to develop a dedicated two-element array coil operating at 300 MHz (7 T) for high-resolution imaging of rat knee joint in order to quantify cartilage thickness and volume. A dedicated two-element array coil with two square elements encompassing knee joint was designed and built. Decoupling between elements was achieved with a capacitor inserted on the common leg of the two elements. The average gain in SNR compared to a 15 mm reference single loop coil was 2.2. This SNR gain was used to improve spatial resolution of 3D acquisition by decreasing the voxel size from 59 x 59 x 156 mum3 to 51 x 51 times 94 mum3 without time penalty. This two element array coil is a key element to perform HR-MRI and extract morphological parameters of animal cartilage. Finally, a set of two array coils were used to perform the acquisition of both rat knee joint at the same time with no additional acquisition time or resolution decrease.

The Ministry of Public Health commissioned a research project to the Catholic University of Leuven and the University Hospital of Liège to revise the Belgian Nursing Minimum Dataset (B-NMDS). The study started in 2000 and will end with the implementation of the revised B-NMDS in January 2007. The study entailed four major phases. The first phase involved the development of a conceptual framework based on a literature review and secondary data analysis. The second phase focused on language development and development of a data collection tool. The third phase focused on data collection and validation of the new tool. In the fourth phase the validity and reliability of the dataset was tested. The new dataset is without avail if it is not leading to new information. Four applications of the dataset has been defined from the beginning: evaluation of the appropriateness of stay (AEP) in the hospital, nurse staffing, hospital financing and quality management. The aim of this paper is to describe how the B-NMDS can contribute to each of these applications.

A key issue in the treatment of many cancers is the development of resistance to chemotherapeutic drugs. Resistance mechanisms are numerous and complex. One of them is mediated by the overexpression of ATP-binding cassette (ABC) transporters able to efflux drugs out of the tumor cell. The last two decades have seen notable growth of knowledge concerning the involvement of ABC transporters in resistance to chemotherapy. This review emphasizes these transporters, their clinical relevance and the diagnostic methods and strategies to circumvent multidrug resistance (MDR) mediated by ABC transporters.

The ATP-binding cassette (ABC) transporters are highly conserved genes involved in the translocation of molecules through biological membranes. Several of them are involved in tumor drug resistance, and it is thought that many others may contribute to the development of the tumor phenotype in a still unknown way. A low-density DNA microarray was recently developed for the analysis of 38 ABC-transporter genes and 3 other transporters. In the present pilot study, clinical samples from 16 breast cancer patients were tested. Of the 41 transporters analyzed, 10 were not or very seldom expressed, while 23 were found to be expressed, sometimes at very high levels, in the majority of the tumors. Comparison of the treated and untreated tumors showed an unexpected similarity of results. The signal obtained on the capture probes for ABCC6/8/9 was, however, found to be higher in the treated samples. The microarray data were validated on 15 ABC-transporter genes by real-time PCR. The present results showed that the expression of the majority of the ABC transporters was a clear feature of breast tumors, whether treated or not.

Objective To determine the magnetic resonance imaging (MRI), macroscopic, and microscopic characteristics of synovial membrane inflammation, to study the relationship between disease severity and the degree of synovial inflammation on MRI and on macroscopic and microscopic examination, and to look for colocalization of chondral lesions and synovial inflammation. Methods Thirty-nine patients with knee osteoarthritis (OA) were classified into 2 groups according to the severity of cartilage lesions as revealed by chondroscopy. Group 1 (n = 14) had mild cartilage lesion(s) without exposure of subchondral bone. Group 2 (n = 25) had severe cartilage lesion(s) with focal or diffuse exposure of subchondral bone. Synovitis was evaluated on T1-weighted MRI sequences according to the degree of synovial thickening on a 4-point scale (ranging from 0 to 3) in 5 regions of interest. Synovial membrane was macroscopically scored, and biopsies were performed on the 5 preselected sites for histologic scoring. Results The mean ± SD synovial thickening score on MRI was 1.55 ± 0.90, with no significant difference between groups 1 and 2. Intra- and interobserver reproducibility of the total synovial score was excellent, and interobserver reproducibility of the MRI grade was good. Synovitis was diffuse and associated with chondral lesions only in the medial femorotibial compartment (r = 0.49, P = 0.001). The degree of synovial thickening on MRI correlated with qualitative macroscopic analysis (rs = 0.58, P < 0.001) and with microscopic features (synovial lining cells [rs = 0.23, P < 0.007], surface fibrin deposition [rs = 0.12, P < 0.01], fibrosis [rs = 0.31, P < 0.006], edema [rs = 0.17, P = 0.07], congestion [rs = 0.30, P < 0.005], and infiltration [rs = 0.46, P < 0.0001]). Fibrin and infiltration parameters were more severe in end-stage disease (P = 0.009 and P = 0.02, respectively). Conclusion Synovitis may be present from the onset of OA and may be evaluated on MRI. MRI evaluation of synovitis could be used to classify OA patients in clinical trials and could help to identify those who could benefit from synovium-targeted therapy.

Summary The process of revising the Belgian Nursing Minimum Dataset (B-NMDS) started in 2000 and entailed four major phases. The first phase (June–October 2002) involved the development of a conceptual framework based on a literature review and secondary data analysis. The Nursing Interventions Classification (NIC) was selected as a framework for the revision of the original B-NMDS. The second phase (November 2002–September 2003) focused on language development for six care programs evaluated by panels of clinical experts ( N =75). These panels identified the following items as priorities for the revised B-NMDS: hospital financing, nurse staffing allocation, assessment of the appropriateness of hospitalisation, and quality management. During this period, we developed a draft instrument with 92 variables using the NIC. This led to an alpha version of a revised B-NMDS. The third phase (October 2003–December 2004) focused on data collection and validation of the new tool. The revised B-NMDS (alpha version) was tested in 158 nursing wards in 66 Belgian hospitals from December 2003 until March 2004. This test generated data for some 95,000 in-patient days. The interrater reliability of the revised B-NMDS was assessed. The criterion-related validity of the revised B-NMDS was compared to that of the original B-NMDS. The discriminative power of the revised B-NMDS was also assessed to select the most relevant variables for data collection. This resulted in a beta version of the revised B-NMDS in December 2004. The records of the revised B-NMDS were linked to the Hospital Discharge Dataset and other mandatory datasets to integrate the revised B-NMDS into the overall healthcare management system. The fourth phase (January 2005–December 2005) is presently focusing on information management. Nationwide implementation is foreseen by January 2007.

This paper describes the process of revising the Belgian Nursing Minimum Data Set (NMDS). The study started in 2000. Implementation is planned from 2006. The project is divided in 4 major phases. The first phase (June-October 2002) implied the development of the conceptual framework based on literature review and secondary data-analysis. The Nursing Interventions Classification (NIC) was selected as framework for the revision of the NMDS. The second phase focused on the language development (November 2002 - September 2003) with panels of clinical experts (N=75) for six care programs. They indicated hospital financing, nurse staffing allocation and assessment of the appropriateness of hospitalization as priorities of a revised B-NMDS. A draft instrument with 84 variables, using NIC, was developed during this period. This leads to an alpha version of a revised NMDS. The third phase (October 2003 - December 2004) focused on the data collection and validation of the new tool. The new NMDS was tested on 158 nursing wards in 66 Belgian hospitals from December 2003 until March 2004. This test generated data for some 95.000 inpatient days. The interrater-reliability of the revised NMDS is tested. The criterion-related validity of the revised NMDS is compared with the actual NMDS. The discriminative power of the revised NMDS is tested to select the most relevant items for data collection. This will result in a beta version of revised NMDS in December 2004. The records of the revised NMDS are linked with the hospital discharge dataset and other mandatory datasets to integrate the revised NMDS in the broader health care management. The fourth phase (January-December 2005) will focus on information management.

To evaluate experimentally the sensitivity of T2 mapping with magnetic resonance (MR) imaging at 8.5 T in depicting variations in proteoglycan content and concurrent extracellular matrix of rat patellar cartilage.The study was performed in 36 immature (age, 5 weeks) and 36 mature (age, 10 weeks) Wistar rats. Maintenance and care of the rats were conducted in accordance with National Institutes of Health guidelines. Fifty-six rats underwent T2 mapping in 28 right patellae degraded with hyaluronidase for 1 and 6 hours and in 28 undegraded age-matched patellae that served as controls. After MR mapping, the rats were sacrificed, and the patellae were studied histologically to evaluate proteoglycan and collagen content and collagen network organization in cartilage. Biochemical analysis was performed in 88 patellae to quantify sulfated glycosaminoglycan and hydroxyproline content. Effects of age and/or degree of degradation were evaluated after rank transformation of continuous data by using rank analysis of variance (ANOVA). Associations between continuous variables were assessed with the Spearman rank correlation coefficient.Results of histologic analysis showed proteoglycan loss after hyaluronidase degradation without alteration of collagen network. No significant variation in hydroxyproline sulfate content was observed with depletion of proteoglycan. Proteoglycan losses of 19% and 13%, found after 1-hour degradation in immature and mature groups, respectively, were associated with significantly increased global T2 values (ANOVA, P.001). Six-hour degradation resulted in more severe proteoglycan losses of 45% and 53% in immature and mature groups, respectively, inducing significant increases in global T2 values in immature and mature groups (ANOVA, P.001). Variations in T2 values between superficial and deep cartilage zones were not affected by proteoglycan depletion.In rat patellar cartilage, T2 mapping permits detection of slight or severe proteoglycan depletion and concurrent changes of extracellular matrix when age-matched samples are compared.

Cartilage engineering consists of re-constructing functional cartilage by seeding chondrocytes in suitable biomaterials in vitro. The characteristics of neocartilage differ upon the type of biomaterial chosen. This study aims at determining the appropriate scaffold material for articular cartilage reconstruction using non articular chondrocytes harvested from rat sternum. For this purpose, the use of polysaccharide hydrogels such as alginate (AA) and hyaluronic acid (HA) was investigated. Several ratios of AA/HA were used as well as three derivatives obtained by chemical modification of HA (HA-C18, HA-C12(2.3), HA-C12(2.5)-TEG0.5). Sternal chondrocytes were successfully cultured in 3D alginate and alginate/HA scaffolds. HA retention in alginate beads was found to be higher in beads seeded with cells than in beads without cells. HA-C18 improved HA retention in beads but inhibited the chondrocyte synthesis process. Cell proliferation and metabolism were enhanced in all biomaterials when beads were mechanically agitated. Preliminary results have shown that the chondrocyte neo-synthesised matrix had acquired articular characteristics after 21 days culture.

The aim of this work was to determine whether Hsp70 overexpression via proteasome inhibitor MG132 was able to protect chondrocytes towards mono-iodoacetate (MIA) cytotoxicity both in vitro and in vivo. In vitro, overexpression of Hsp70 via MG132 was significantly able to protect chondrocytes from MIA toxicity (MTT/LDH analyses). Hsp70 essentially mediated this chondroprotective effect as demonstrated by antisense strategy. In vivo, chondrocytic overexpression of Hsp70, after a preventive intra-articular injection of MG132 in rat knee, was sufficient to decrease the severity of OA-induced MIA lesions, as demonstrated histologically and biochemically. In conclusion, intracellular overexpression of Hsp70, through proteasome inhibition, could be an interesting tool in protecting chondrocytes from cellular injuries, either necrotic or apoptotic in nature, and thus might be a novel chondroprotective modality in rat experimental OA.

To evaluate the ability of MR T2 mapping (8.5 T) to characterize ex vivo longitudinally, morphologically and quantitatively, alginate-based tissue engineering in a rat model of patellar cartilage chondral focal defect. Calibrated rat patellar cartilage defects (1.3 mm) were created at day 0 (D0) and alginate sponge with (Sp/C+) or without (Sp/C−) autologous chondrocytes were implanted. Animals were sacrificed sequentially at D20, D40 and D60 after surgery and dissected patellae underwent MRI exploration (8.5 T). T2 values were calculated from eight SE images by using nonlinear least-squares curve fitting on a pixel-by-pixel basis (constant repetition time of 1.5 s, eight different echo times: 5.5, 7.5, 10.5, 12.5, 15.0, 20.0, 25.0 and 30.0 ms). On the T2 map, acquired in a transversal plane through the repair zone, global T2 values and zonal variation of T2 values of repair tissue were evaluated versus control group and compared with macroscopic score and histological studies (toluidine blue, sirius red and hematoxylin-eosin). “Partial”, “total” and “hypertrophic” repair patterns were identified. At D40 and D60, Sp/C+ group was characterized by a higher proportion of “total” repair in comparison to Sp/C− group. At D60, the proportion of “hypertrophic” repair was two fold in Sp/C− group versus Sp/C+ group. As confirmed morphologically and histologically, the T2 map also permitted the distinction of three types of repair tissue: “total”, “partial” and “hypertrophic”. “Total” repair tissue was characterized by high T2 values versus normal cartilage (p

As the mixture cremophor/ethanol is known to have side-effects affecting the peripheral nervous system, we have assessed its behavioural and morphological neurotoxicity after repeated intraperitoneal injections in male Sprague Dawley rats. Clinical status of the animals was good throughout the experiment and no motor deficits were observed. Nevertheless, sensory testing demonstrated an hyperalgesia and an allodynia to mechanical stimuli, associated to peripheral axon degeneration.

Using doses close to those used clinically, we have developed an animal model of vincristine-induced nociceptive sensory neuropathy after repeated intravenous injection in male Sprague-Dawley rats. In order to validate the model, three different doses (50, 100 and 150 microg/kg) of vincristine were injected every 2nd day until five injections had been given. The sensory behavioural assessment revealed mechanical hyperalgesia and allodynia associated with cold thermal hyperalgesia and allodynia. With regard to electrophysiological evaluation, we observed a decrease in the nerve conduction velocity in the highest dose group. Morphological studies revealed few degenerated fibers in the sciatic nerve and many degenerated myelinated axons in the fine nerve fibers of the subcutaneous paw tissue. Finally, to develop an animal model, we chose the 150 microg/kg dose because of the good general clinical status of the rats without motor function changes associated with severe sensation disorders like hyperalgesia and allodynia. This model of vincristine-induced painful neuropathy will be used to explore physiopathological mechanisms implied in the genesis of neuropathic pain and also to test new analgesic and neuroprotective drugs.

Objective To investigate the influence of a calibrated exercise on the progression of structural lesions in an experimental model of osteoarthritis (OA) in the rat, and to explore the effect of exercise on the level of chondrocyte caspase-dependent apoptosis and of Hsp70. Methods The OA model was induced by anterior cruciate ligament transection (ACLT). Rats were placed in 4 experimental groups: operated (ACLT) free moving rats, and 3 exercise groups (slight, moderate and intense) subjected to running training. Rats were killed 14 and 28 days after surgery. Results On D14 histological assessment demonstrated a beneficial influence of a slight and a moderate exercise vs control ACLT group. Hsp70 increased significantly in the moderate group vs controls. On D28, histological lesions strongly decreased in the slight and moderate exercise groups vs ACLT group, while an intense effort abolished this beneficial trend. Interestingly, the concomitant course of apoptotic events (caspase 3-positive cells) and the co-expression of Hsp70 in the various groups varied, when significant, in an inverse manner. In the intense group this overexpression was not noted, as a "burn out" appeared, thus leading to a loss of this protective effect. Conclusion This study shows that a calibrated slight or moderate exercise exerts a beneficial influence on the severity of chondral lesions in ACLT rats. Conversely, a strong effort abolishes this chondroprotective effect. This effect could be related to a reduced level of chondrocyte apoptosis through anti-apoptotic capacities of stress-induced Hsp70 overexpression.

An 80-year-old man treated by levofloxacin developed multiple tendon ruptures. His symptoms resolved over 9 months after levofloxacin discontinuation. Nasal corticosteroid therapy, aging and chronic respiratory insufficiency were probably predisposing factors in this patient.

To establish a system for efficient direct in vivo gene targeting into rat joint, we have evaluated a strategy of gene transfer by means of the delivery of external electric pulses (EP) to the knee after intra-articular injection of a reporter gene (GFP). Rats were killed at various times after the electro gene-therapy to analyze GFP gene expression by immunohistochemistry. GFP staining was detected in the superficial, middle, and deep zones of the patellar cartilage at days 2 and 9, and thereafter only in the deep zone (months 1 and 2). The average percentage of GFP-positive cells was estimated at 30% both one and 2 months after the gene transfer. Moreover, no pathologic change caused by the EP was detected in the cartilage. The level and stability of the long-term GFP expression found in this study demonstrate the feasibility of a treatment of joint disorders (inflammatory or degenerative, focal or diffuse) using electric gene transfer.

To evaluate any inhibitory effect of a single dose of human recombinant interleukin-1 beta (hrIL-1 beta) on the severity of carrageenan-induced oedema in rats (a commonly used model of acute inflammation), we first injected 0.1 ml of carrageenan (0.2%, 0.5%, or 2%) to induce mild, moderate, or severe inflammation, respectively into the right rear footpad. Then we promptly injected the interleukin (0.02, 0.2, or 2 micrograms) subcutaneously into the flank. The initial rapid increase in volume of the injected paw (within 2 h of the subplantar injection) was independent of the dose of carrageenan, whereas the increase in volume by 6 to 10 h was dose-dependent. All doses of HrIL-1 beta inhibited the carrageenan-induced swelling at the 6th hour. In the moderate and severe carrageenan-induced oedemas, the higher dose of HrIL-1 beta induced a delayed inflammation peaking at 10 h instead at 6 h.

A study was undertaken to assess the availability and use of non-invasive ventilation (NIV) for the treatment of acute exacerbation of chronic obstructive pulmonary disease (COPD) in emergency departments in Belgium. A questionnaire was sent to the head physicians of 145 emergency departments (EDs) found in the list of the Belgian College of Emergency Physicians (BeCEP). Ninety eight questionnaires were analysed (representing 68% of the questionnaires sent). NIV was used in 49% of the EDs. In the hospitals where NIV was not used, the most important reasons given were no available equipment in 71%, lack of experience with this form of treatment in 32.7%, and more time consuming for physicians and nursing staff in 22.8%. Only 3.8% of the physicians doubted the benefit of NIV treatment. In the hospitals where NIV was used, the patient was watched during the first hour by one nurse only in 19.6%, by one physician in 8.6% and by a nurse and a physician in 54.5%. NIV was used for more than 4 h in 33% of EDs. Pressure-controlled ventilation (with home respirators) was used more often than volume-controlled ventilation.

The MR aspect of articular cartilage, that reflects the interactions between protons and macromolecular constituents, is affected by the intrinsic tissue structure (water content, the content of matrix constituents, collagen network organization), imager characteristics, and acquisition parameters. On the T1-weighted sequences, the bovine articular cartilage appears as an homogeneous tissue in high signal intensity, whatever the age of animals considered, whereas on the T2-weighted sequences, the articular bovine cartilage presents variations of its imaging pattern (laminar appearance) well correlated to the variations of its histological and biochemical structure. The T2 relaxation time measurement (T2 mapping), which reflects quantitatively the signal intensity variations observed on T2 weighted sequences, is a way to evaluate more precisely the modifications of cartilage structure during the aging and maturation processes (rat's study). This technique so far confined to experimental micro-imagers is now developed on clinical imagers. Consequently, it may permit to depict the early stages of osteoarthritic disease (OA) or to evaluate the chondroprotective effect of drugs.

Since the antipyretic and probably the analgesic effects of paracetamol are, at least in part, centrally mediated, its plasma and cerebrospinal fluid (CSF) concentrations were measured in 43 patients with nerve-root compression pain. Each subject was given a short i.v. infusion of 2 g propacetamol, a prodrug which is hydrolysed to paracetamol within 7 min. Single blood and CSF samples were drawn concomitantly in each patient at intervals between 20 min and 12 h. Maximum CSF drug concentrations were observed at the 4th hour, subsequent concentrations exceeding those in plasma. The elimination half-life of paracetamol calculated from pooled data was shorter in plasma (2.4 h) than in CSF (3.2 h). The time-course of paracetamol in CSF may parallel that of analgesic effect.

This study was designed to investigate the pathways involved in neurogenic-mediated articular cartilage damage triggered by a nonsystemic distant subcutaneous or intra-articular inflammation. The cartilage damage was assessed 24 h after subcutaneous or intra-articular complete Freund's adjuvant (CFA) injection measuring patellar proteoglycan (PG) synthesis (ex vivo [Na2 35SO4] incorporation) in 96 Wistar rats. Unilateral subcutaneous or intra-articular injection of CFA induced significant decrease (25–29%) in PG synthesis in both patellae. Chronic administration of capsaicin (50 mg · kg−1 · day−1 during 4 days), which blunted the normal response of C fiber stimulation, prevented the bilateral significant decrease in cartilage synthesis. Similarly, intrathecal injection of MK-801 (10 nmol/day during 5 days), which blocked the glutamatergic synaptic transmission at the dorsal horn of signal originating in primary afferent C fibers, eliminated the CFA-induced PG synthesis decrease in both patellae. Chemical sympathectomy, induced by guanethidine (12.5 mg · kg−1 · day−1 during 6 wk), also prevented PG synthesis alteration. Finally, compression of the spinal cord at the T3-T5 level had a similar protective effect on the reduction of [Na2 35SO4] incorporation. It is concluded that the signal that triggers articular cartilage synthesis damage induced by a distant local inflammation 1) is transmitted through the afferent C fibers, 2) makes glutamatergic synaptic connections with the preganglionic neurons of the sympathetic system, and 3) involves spinal and supraspinal pathways.

Keywords: Mri ; cartilage ; articular contact ; morphology ; rat ; Articular-Cartilage Reference EPFL-CONF-169141doi:10.1080/10255840802298786View record in Web of Science Record created on 2011-09-29, modified on 2017-05-12

SummaryFamilial calcium pyrophosphate dihydrate deposition disease (CPPDD) is a disease of articular cartilage that is radiographically characterized by chondrocalcinosis due to the deposition of calcium-containing crystals in affected joints. We have documented the disease in an Argentinean kindred of northern Italian ancestry and in a French kindred from the Alsace region. Both families presented with a common phenotype including early age at onset and deposition of crystals of calcium pyrophosphate dihydrate in a similar pattern of affected joints. Affected family members were karyotypically normal. Linkage to the short arm of chromosome 5 was observed, consistent with a previous report of linkage of the CPPDD phenotype in a large British kindred to the 5p15 region. However, recombinants in the Argentinean kindred have enabled us to designate a region

Since dimethicone may be employed to improve gastrointestinal tolerability of non steroidal anti-inflammatory drugs (NSAIDs), we studied its influence on the pharmacokinetics of ketoprofen in subjects receiving a single oral dose of racemic ketoprofen.In a cross-over experimental design, 12 healthy fasting volunteers were given a single oral dose (100 mg) of racemic ketoprofen, administered with or without dimethicone. The kinetic parameters measured were area under the concentration (AUC), maximum peak plasma concentration (Cmax), time to reach peak concentration (tmax), elimination half-life (t1/2), mean residence time (MRT) and urinary excretion for R and S enantiomers.Dimethicone reduced the peak concentration of both R and S ketoprofen by about 10% (P0.05) and also induced a slight but non-significant increase in the mean time to achieve peak concentration. However, this treatment had no significant effect on the bioavailability and the elimination of R and S enantiomers, as shown by AUC, t1/2 and MRT values. The absorption patterns were equivalent for both ketoprofen isomers, since plasma pharmacokinetic parameters were similar. Nevertheless, the urinary recovery was significantly lower for R ketoprofen than for its antipode. The administration of dimethicone did not alter this stereoselectivity.The administration of dimethicone to alleviate the epigastralgic effects related to NSAIDs does not affect the efficacy of the treatment. Dimethicone did not significantly alter the bioavailability of ketoprofen, chosen as an example of an NSAID, especially that of the pharmacologically active S enantiomer.

We assessed the time-course of adjuvant arthritis (AA) in Lewis rats, using biotelemetry to monitor the rat’s spontaneous locomotor activity and body temperature, and studied the evolution of the arthritic index, circulating concentrations of inflammation-promoting cytokines, cartilage proteoglycan synthesis, and the effect of indomethacin as a cyclooxygenase inhibitor to evaluate prostaglandin (PG) contribution in AA. The injection of complete Freund’s adjuvant on day 0( D0) induced a marked, transient loss of locomotor activity ( D1– D4; initial phase) and then a second phase of hypomobility peaking on D15 and thereafter irreversible ( D16– D20; arthritic phase). Fever peaked first on D1 and again between D13 and D17. The primary hyperthermia was associated with increases in plasma interleukin-6 and tumor necrosis factor-α concentrations and seemed to be partly PG dependent. Proteoglycan synthesis inhibition in the patellar cartilage increased gradually, spreading from the injected paw to the contralateral paw. It was corrected on D20 by preventive and curative indomethacin treatments. Indomethacin also greatly relieved hypomobility during the systemic phase of AA ( D10– D15). The combination of information about cartilage metabolism, body temperature, locomotor activity, and cytokine in this study permits analysis of analgesic, antipyretic, anti-inflammatory, and chondroprotective properties of drugs in the various phases of AA. Thus, using a new methodology, we have discriminated the different phases of the disease and confirmed the symptomatic and systemic inhibitory effect of indomethacin on fever, activity, and cartilage metabolism.

No effective systemic therapy exists for patients with advanced hepatocellular carcinoma (HCC). Surgery is the mainstay treatment for patients with early stage HCC tumors. Either resection or transplantation is advocated if the HCC is within the Milan criteria. Nonsurgical treatments including percutaneous ethanol injection, radiofrequency ablation, and transcatheter arterial chemoembolization (TACE) are used as adjuvant therapy to surgery but also to treat unresectable HCC. Although a meta-analysis showed a beneficial survival effect for patients with intermediate HCC treated by TACE using doxorubicin and cisplatin, the survival benefit of systemic chemotherapy for the treatment of liver cancer is marginal at best. Although Sorafenib, a multi-tyrosine kinase inhibitor, is becoming established as the first line of therapy for advanced HCC, it was recently shown to be a substrate of ABCB1 and ABCG2, two major transporters involved in multidrug resistance (MDR) and expressed in hepatocytes. In this study, the MDR transcriptome was analyzed in a cohort of 38 patients using TaqMan-based qRT-PCR, with the aim of finding ways to sensitize this intrinsically MDR cancer. The study reveals a 45-gene signature, validated using an independent cohort of 53 patients, that predicts overall survival (OS). We used the Connectivity Map tool, designed to reveal connections among drugs, genes, and pathological states, to identify three compounds that converted the gene expression profile of HCC cell lines from one matching patients with poor OS to one with good OS. These compounds increased histone acetylation, resulting in the sensitization of tumor cells to conventional chemotherapy including cisplatin, sorafenib and 5-FU. This work provides new treatment strategies based on gene expression profiling and connectivity data for a disease for which no effective systemic treatments exist. More importantly, the current study reveals a new strategy to sensitize any type of refractory cancer to chemotherapy. Citation Format: Jean-Pierre Gillet, Jesper B. Andersen, James P. Madigan, Sudhir Varma, Chung-Pu Wu, Anna M. Calcagno, Suresh V. Ambudkar, Snorri S. Thorgeirsson, Michael M. Gottesman. Multidrug resistance transcriptome analysis highlights compounds that sensitize resistant hepatocellular carcinoma through increased histone acetylation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 954. doi:10.1158/1538-7445.AM2013-954

Inhibition of histone deacetylase (HDAC) enzymes represents a promising therapeutic approach in clinical oncology, as aberrant gene expression and alterations in histone acetylation due to HDACs have been implicated in tumor development and progression. Even though several histone deacetylase inhibitors (HDIs) are currently in clinical trials, so far only the HDIs romidepsin and vorinostat have been approved by the U.S. Food and Drug Administration for the treatment of cutaneous T-cell lymphoma (CTCL). During clinical trials with romidepsin in CTCL, disease progression was noted in some patients who initially responded to therapy, while the disease in other patients did not respond to therapy suggesting that both de novo and acquired resistance to romidepsin were observed. To identify molecular determinants of resistance, we selected HuT78 CTCL cells with romidepsin in the presence of inhibitors of P-glycoprotein (Pgp) to prevent upregulation of Pgp as a mechanism of resistance. Resistant sublines were approximately 250- to 385-fold resistant to romidepsin; the Pgp inhibitor tariquidar did not significantly reverse resistance. The sublines also exhibited resistance to apoptosis following treatment with the HDIs apicidin, belinostat, entinostat, panobinostat, and vorinostat. A custom gene-expression array detected elevated expression of insulin receptor (INSR) in romidepsin resistant cells compared to parental cells. Immunoblot analysis of downstream effectors of the IR pathway demonstrated a 4- to 8-fold increase in mitogen-activated protein kinase (MAPK) kinase (MEK) phosphorylation. Even though resistant cells did not respond to 48 h treatment with inhibitors of the insulin receptor, they exhibited exquisite sensitivity to treatment with as little as 1 nM of the MEK inhibitor PD0325901. Sensitivity to MEK inhibition in resistant cells was associated with restoration of the pro-apoptotic protein Bim. Combined treatment of romidepsin with MEK inhibitors also significantly yielded greater apoptosis in resistant cells compared to romidepsin and MEK inhibitor treatment alone. Gene expression analysis of circulating tumor samples obtained from patients with CTCL enrolled on the NCI 1312 Phase II romidepsin study suggested interaction of romidepsin with the MAPK pathway, indicated by altered expression of genes demonstrated to be under its control. These findings implicate activation of MEK as a resistance mechanism to romidepsin, and suggest combination of romidepsin with MEK inhibitors in clinical trials. Citation Format: Arup R. Chakraborty, Rob Robey, Zhirong Zhan, Victoria Luchenko, Michael Gottesman, Nathan Collie, Jean-Pierre Gillet, Richard Piekarz, Andrew Kossenkov, Louise Showe, Susan Bates. Resistance to the histone deacetylase inhibitor romidepsin is associated with degradation of Bim following MAPK pathway activation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3399. doi:10.1158/1538-7445.AM2013-3399

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The direct 5-lipoxygenase inhibitor L-739,010 was administered at a dose of 60 mg/kg/day per os to beagle dogs for 15 days. Histopathological examination of gallbladders from treated dogs showed epithelial vacuolation and submucosal infiltration by foamy macrophages that were positive for lipids in Sudan Black-and/or Oil Red O-stained sections. Scanning electron microscopic examination of gallbladder mucosa showed thickening of epithelial folds and multifocal epithelial membrane disruptions. Transmission electron microscopy confirmed these findings and showed mucosal epithelial cell lipid droplet accumulation and submucosal infiltration of macrophages filled with lipid droplets, myelin figures, heterophagosomes, and cholesterol clefts. These changes resembled those reportedly seen in the human gallbladder with cholesterolosis and/or chronic cholecystitis.

The aim of this study was to document the accuracy of magnetic resonance imaging (MRI) during fluoroquinolone-associated Achilles tendinitis. Fourteen Achilles tendons were examined by MRI (T1 and T2 or T2 * -weighted sequences) in nine patients with typical tendinopathy (13 cases of tendinitis and 1 rupture) during fluoroquinolone therapy. Tendinous involvement was classified according to the prominence of intra- or peritendinous changes. The most typical feature was the presence of intratendinous changes, longitudinal or transversal, detected on T1 or T2-weighted sequences. Peritendinitis was most visible in two cases and nodular involvement in three cases. It was concluded that MRI appears a helpful and accurate method in identifying and classifying such iatrogenic tendinitis. In addition, MRI indicates orthopedic management when detecting risk of rupture

Spontaneous corneal deposits, characterized by the presence of multiple basophilic granules at the basis of the corneal epithelium, are well described in different rat strains (1, 19) but in the literature a variation in terminology is found: i.e. corneal degeneration (1), corneal opacities (12), corneal dystrophy (19) or band keratopathy (33). This pathology is not unique to the rat but has been described in various other laboratory animals such as mouse (34), rabbit (11, 13) and dog (associated to hyperadrenocorticism, 31), as well as in man in which comparison is often done with band keratopathy (1).

The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy.

Acquired and intrinsic resistance to histone deacetylase inhibitors (HDIs), a new targeted group of anti-tumor agents, limits their clinical efficacy. A detailed understanding of the mechanisms of resistance to HDIs may lead to strategies designed to increase clinical efficacy. To investigate molecular mechanisms of resistance to the HDI romidepsin (Dp), we studied a cutaneous T-cell lymphoma (CTCL) cell line, HuT 78, independently selected in verapamil (Vp) or valspodar (PSC833) to prevent the emergence of P-glycoprotein (Pgp), a known resistance mechanism. The HuT 78 sublines DpVp 50 and DpP 75 display 100-200-fold resistance to romidepsin, not due to Pgp expression. A custom-made Taqman low density gene expression array detected increased expression of insulin receptor (IR) in the resistant cells. Real-time PCR analysis confirmed the results of gene array and detected more than 50-fold upregulation of IR in the romidepsin-selected cells compared to the parental cells. Increased phosphorylation (5- to 8- fold) of mitogen activated protein kinase kinase (MEK), a downstream effector of the IR pathway, was also observed in the resistant cells compared to the parental cells. While HuT 78 cells were insensitive to MEK inhibition, resistant cells were found to be exquisitely sensitive to MEK inhibition (IC50 < 10 nM) but not to phosphatidylinositol 3-kinase (PI3K) inhibition. Combined treatment of romidepsin with low concentrations (1- 3 nM) of MEK inhibitor also resulted in increased cell death in romidepsin-resistant HuT 78 cells. The exquisite sensitivity to MEK inhibition in the resistant sublines was found to correlate with restoration of the expression of Bim (BCL2L11), a Bcl-2-homology domain-3 only (BH-3) proapoptotic protein. In the resistant cells, the MAPK pathway appeared to regulate Bim expression posttranslationally as we did not detect any gene induction of BCL2L11 or FOXO3, a transcription factor known to activate BCL2L11 expression, following MEK inhibition. These findings implicate increased activation of the MAPK pathway as a mechanism of resistance to romidepsin, and suggest that combining romidepsin with MEK inhibitors may be an effective strategy to overcome resistance.

Resume La vie du pere Vincent Lebbe, apotre de la Chine et promoteur de l’episcopat indigene, a ete largement documentee, commentee et critiquee depuis la parution de sa biographie par le Chanoine Jacques Leclercq en 1955. Par contre, on connait peu son disciple, l’abbe Andre Boland qui a voulu, dans les annees 1930-1940 realiser un des souhaits des premiers eveques chinois : envoyer en Chine des pretres diocesains europeens pour œuvrer avec les pretres chinois au service de l’episcopat “indigene”. En depouillant les archives conservees a la Sam a Bruxelles, on peut lever un coin du voile sur le “parcours du combattant” de l’abbe Boland, ses luttes et ses difficultes, plusieurs decennies avant l’encyclique Fidei Donum qui ouvrira au clerge europeen la possibilite de partir « en missions ».