Encapsulation capacity and natural payload delivery of an anticancer drug from boron nitride nanotube.

The behavior of confined anticancer carboplatin (CPT) molecules in a single (10, 10) boron nitride nanotube (BNNT) was studied by means of molecular dynamics simulations. Our study revealed a very large storage capacity of BNNT. Analysis of the energy profiles depending on the number of confined molecules, and on their spatial organization allowed us to quantify the ability of BNNT to vectorize CPT. Indeed, BNNT despite its small radius presented a large inner volume that favored stable encapsulation of multiple active anticancer molecules. Moreover, in our molecular dynamics simulations, the empty BNNT and the BNNT filled with CPT diffused spontaneously to the cell membrane and were able to passively enter inside lipid bilayers by a lipid-assisted mechanism. This property has been used to deliver naturally anticancer drugs to cellular targets. Using this enhanced drug delivery system, we have provided a definitive solution to the problem of drug release and have thus opened up a new way of targeting cancer cells. Indeed, regardless of the mode of action of the platinum complex towards the cell, the delivery of the drug on site should limit the side effects of the drug.

[Gout, revisited]. / La goutte, revisitée.

In recent decades, gout became the most common inflammatory arthritis and one in which pathogenesis and risk factors are best understood. One of the treatment objectives in current guidelines is "cure". However, audits show that minority of patients with gout receive adequate advice and treatment. Doctors often focus on managing acute attacks rather than viewing gout as a chronic progressive crystal deposition disease. Accordingly, urate-lowering treatment is underprescribed and often underdosed. The recent introduction of a panel of new treatments of gout and a better understanding of epidemiologic factors (such as the fructose) may improve management of this easily diagnosed and curable form of potentially severe arthritis, worsening probably the cardiovascular prognostic.

[Ultrasonography and rheumatology]. / L'échographie dans la pratique rhumatologique.

Muskuloskeletal ultrasound has been incorporated by rheumatologist to the clinical practice over the past decade. The technical improvements of the devices allowed the production of high quality images contributing to better identification of joint inflammation and structural damage. In this review, we highlight the applications of ultrasound in the study of different rheumatic conditions.

[Early referral of first line patients suspected of axial spondyloarthritis: the Belgian results of the RADAR study]. / Renvoi précoce au spécialiste de patients avec une suspicion de spondyloarthropathie axiale en première ligne: les résultats belges de l'étude RADAR.

Currently, there is a 5 to 7 years gap between the first symptoms and the diagnosis of ankylosing spondylitis. A better patient referral might reduce this gap and accelerate the adequate treatment implementation. The study objective was to compare 2 referral strategies used in first line. In Belgium, 208 referral physicians assigned to 16 rheumatology centres were randomized to refer chronic back pain patients (with onset <45 years) using 1 of the 2 referral strategies: Strategy 1 :1 of 3 criteria (inflammatory back pain, HLA-B27, sacroiliitis on imaging); or Strategy 2: 2 of6 criteria (IBP inflammatory back pain, HLA-B27, sacroiliitis, family history, good response to NSAIDs, extra-articular manifestations). Among the 141 referred patients with strategy 1 and 2, 26.0 and 36.9% respectively were diagnosed with Axial Spondylarthritis (SpA). Inflammatory back pain, sacroiliitis and good respond to NSAIDs were the most frequently used criteria (92.9 %, 36.2 % and 33.3% respectively). This study emphasizes the high prevalence of undiagnosed axial SpA in patients with chronic back pain and stressed the necessity to increase awareness of the disease.

Bio-optimized Curcuma longa extract is efficient on knee osteoarthritis pain: a double-blind multicenter randomized placebo controlled three-arm study.

OBJECTIVES: Comparison of two doses of bio-optimized Curcuma longa extract (BCL) in the management of symptomatic knee osteoarthritis (OA). METHODS: A prospective, randomized, 3-month, double-blind, multicenter, three-group, placebo-controlled trial assessing Patient Global Assessment of Disease Activity (PGADA) and serum sColl2-1, a biomarker of cartilage degradation, as co-primary endpoints. Pain on visual analog scale (VAS), Knee injury and Osteoarthritis Outcome Score (KOOS), and paracetamol/non-steroidal anti-inflammatory drug (NSAID) consumption were used as secondary endpoints. RESULTS: One hundred fifty patients with knee OA were followed for 90 days. Low and high doses of BCL showed a greater decrease of PGADA than placebo. Analysis of sColl2-1 showed in the placebo and BCL low-dose groups, but not in the BCL high-dose group, a transient but non-significant increase of sColl2-1 between T0 and T1. Thereafter, in all groups, sColl2-1 decreased between T1 and T3 (all p < 0.01), but no difference between the groups was found. Pain reduction at day 90 in the low- and high-dose BCL groups (- 29.5 mm and - 36.5 mm) was higher than that in the placebo (- 8 mm; p = 0.018). The global KOOS significantly decreased overtime, but changes were comparable across treatment arms. The ratio of patients with adverse events (AE) related to the product was similar in the placebo and treatment groups, but the number of AE linked to the product was higher in the high-dose BCL group compared to the placebo (p = 0.012). CONCLUSIONS: BCL appeared safe and well-tolerated with no evidence of severe adverse effects. Efficacy analysis suggested positive trends for measurements of PGADA and serum levels of an OA biomarker and showed a rapid and significant decrease of pain in knee OA (Trial registration: ISRCTN, ISRCTN12345678. Registered 21 September 2016-retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02909621?term=osteoarthritis+curcumin&rank=5-Evaluation of FLEXOFYTOL® Versus PLACEBO (COPRA) NCT02909621).

Low back pain as presenting manifestation of giant cell arteritis associated to abdominal aortitis.

Giant cell arteritis (GCA) is the most common vasculitis in Western countries in individuals over the age of 50. The diagnosis is relatively straightforward when typical features, such as headache, jaw claudication or other ischemic complications are present. Although atypical presentations of GCA have been described, herein we report for first time low back pain as the presenting manifestation of this vasculitis. We also emphasize the importance of considering the use of positron emission tomography (PET) in the evaluation of GCA patients presenting without "overt" cranial ischemic manifestations.

[Early rheumatoid arthritis (ERA) diagnosis]. / Le diagnostic de l'arthrite rhumatoïde précoce (ARP).

The rheumatoid arthritis (RA) diagnosis is based on the ARA criteria, even though the radiological joint erosions are often a requirement to make a definite diagnosis. The early rheumatoid arthritis (ERA) concept was thought of following the poor therapeutic response of the established RA. The "window of opportunity" is defined as a time frame in the early phase of the disease in which the therapeutic response is favoured, and thus giving a real chance to modify the course and the prognosis of RA. To achieve such a goal, new imaging modalities have been developed (MRI and Musculoskeletal ultrasonography--MSU), together with new serologic, inflammatory markers, genetic tests and taking into account the environmental impact (such as tobacco smokers). Such an issue can be achieved with a tight collaboration between the primary care physician and the rheumatology speciality care.

[The treatment of psoriasis: basic principles and new options]. / Le traitement du psoriasis: sa stratégie et les nouvelles options.

Psoriasis is a frequent chronic disease with a typical cutaneous expression described as erythemato-squamous lesions, and sometimes, joint involvement. This disorder rarely causes death in patients, but often alters their quality of life. A better understanding of the pathophysiology of psoriasis has led to the development of new therapeutic options among which are treatments targeted on blocking T-cell activation. Thanks to these therapies we can offer the patients long lasting remission, albeit not a curative approach. The therapeutic approach towards psoriasis will be selected in a multidisciplinary spirit, and after considering the patient himself, his disease and his lifestyle.

Mechanism of action of cyclosporin in rheumatoid arthritis.

Heterogenous population of cells, including macrophages, synoviocytes and lymphocytes play important roles in the immunopathogenesis of rheumatoid arthritis (RA). T cells, however, seem to be a common thread throughout the disease process. In inhibiting T lymphocytes, cyclosporin A presents a more selective form of therapy in RA. The immunosuppressive action of cyclosporin is primarily due to the inhibition of antigen/mitogen-induced secretion of lymphokines at the transcriptional level from T cell. The inhibition of Ca2(+)-dependent signaling pathways by cyclophilin-cyclosporin complexes in T cell appears to shut down lymphokine-gene transcription.

[Treatment of rheumatoid arthritis: current and future]. / Le traitement de la polyarthrite rhumatoïde: présent et futur.

Rheumatoid arthritis (RA) is a chronic articular inflammatory disease of unknown aetiology. The therapeutic approach can be achieved at different levels: 1) symptomatic treatment with nonsteroidal anti-inflammatory drugs which can relieve articular pain and stiffness, 2) second-line drugs (or DMARD, for Disease Modifying Anti-Rheumatic Drug) selected for their capacity to slow the rheumatoid process. During this last decade, sulfasalazine and methotrexate became an alternative choice to the "classical" slow-acting antirheumatic drugs such as gold, D-penicillamine or antimalarials. The extensive progress in basic immunology and especially in the immunopathology of RA has allowed the elaboration of a new approach to immunotherapy, aimed at molecular targets on cells from the "specific immunity" system or against mediators of the inflammatory process, such as the cytokines.

T cell proliferation induced by anti-CD3 antibodies: requirement for a T-T cell interaction.

In the presence of interleukin 2 (IL2), soluble anti-CD3 monoclonal antibodies can stimulate highly purified normal T lymphocytes to proliferate. In these experiments HLADR+ T cells constituted 13 to 20% of the total cell population, and other HLADR+ cells, such as monocytes and B lymphocytes, constituted less than 1% of the population. When the HLADR+ T cells were removed from the total T cell population by cytofluorometric sorting, the residual HLADR- T cells failed to respond to soluble anti-CD3 plus IL2. When the separated HLADR+ T cells were recombined with the HLADR- T cells, a response was again found. This response was dependent on the dose of HLADR+ T cells added in the mixture. Irradiation individually of the HLADR+ and DR- T cells revealed that the proliferation in the cell mixture was predominantly, if not exclusively, by the HLADR- T cells. The ability of the HLADR+ T cells to provide a signal necessary to this proliferation was radioresistant. These data indicate that under the conditions of these experiments HLADR+ ("activated") T cells provide a signal necessary to the responsiveness of previously resting T cells.

Heterogeneity of immunoregulatory T cells in human thyroid autoimmunity: influence of thyroid status.

Monoclonal antibodies of the OKT series were used to identify circulating T lymphocytes (OKT3+), their helper-inducer (OKT4+) and suppressor-cytotoxic (OKT8+) subsets and cells bearing Ia antigen (OKIa+) in 75 patients with thyroid autoimmune disorders, including 14 Graves' disease, 21 myxoedema, 20 asymptomatic thyroiditis, 12 Hashimoto's thyroiditis and eight simple goitre with superimposed thyroiditis. In the whole population of patients, a negative correlation was observed between the percentage of OKT8+ cells and serum free thyroxine levels whatever the type of thyroiditis. The percentage of OKT8+ cells was decreased in Graves' disease and increased in myxoedema while it reversed after adequate treatment of the two diseases. However, a trend to a decrease in the proportion of OKT8+ cells was still observed in treated Graves' disease and in all the other groups of thyroiditis with euthyroidism. The minor modifications observed for OKT3+ and OKT4+ cells were in relation with those of OKT8+ cells. There was an increased percentage of Ia+ cells in Graves' disease and in Hashimoto's thyroiditis partly reflecting the presence of activated lymphocytes. In conclusion, these data suggest first of all a direct influence of serum T4 on the distribution of circulating OKT8+ cells in addition to documenting the heterogeneity of T cell immunoregulatory factors.

Study of magnetic resonance imaging in transient osteoporosis of the hip.

To better define the magnetic resonance imaging (MRI) features during transient osteoporosis of the hip, we carried out sequential MRI of 8 patients with transient osteoporosis of the hip showing the typical radiographic pattern of diffuse osteoporosis of the femoral head. These cases displayed the same MRI changes in the femoral head and neck characterized by low signal intensity on the T1 weighted images and high signal intensity on the T2 weighted images. The MRI signal became normal within 11 months, but surprisingly, migration of the MRI abnormalities was observed during the course of the disease in 5 cases: abnormal MRI signals were first observed in the anterior area, then migrated to the posterior part, while a normal MRI signal reappeared in the anterior part. We conclude that MRI seems to show some particular features in transient osteoporosis of the hip, which normalize after a few months of evolution; this could represent a migration of MRI abnormalities. Such findings could help in the differential diagnosis of hip diseases such as aseptic bone necrosis.

Polymorphonuclear neutrophils enhance anti-CD3-induced T cell activation: the role of polymorphonuclear FC-receptors.

We investigated the effect of polymorphonuclear neutrophils (PMN) on anti-CD3 mAb (OKT3 and anti-Leu4)-mediated T cell activation. In the absence of monocytes, purified E-rosette-positive cells (further referred to as "T cells") require either solid-phase bound anti-CD3 or the combination of both a high concentration of soluble anti-CD3 and exogenous recombinant interleukin 2 (rIL-2) to proliferate. PMN cannot sustain T cell proliferation with soluble anti-CD3, but they markedly boost proliferation in the presence of soluble anti-CD3 and rIL-2. When PMN were added to T cell cultures stimulated with anti-CD3, this resulted in IL-2 receptor (IL-2R) expression and CD3 modulation. The mechanism of enhancement of anti-CD3-induced IL-2-responsiveness by PMN was further analyzed. A cellular T cell-PMN interaction was found to play a critical role and this was mediated through PMN Fc receptors (FcR). PMN bear two types of low-affinity FcR (FcRII and FcRIII). FcRII is known to bind mIgG1 (e.g., anti-Leu4) and FcRIII binds mIgG2a (e.g., OKT3). FcR involvement was demonstrated by two observations. Anti-FcRII mAb IV.3 inhibited the PMN signal for T cell activation with anti-Leu4. PMN bearing the second variant of FcRII which is unable to bind mIgG1 failed to promote anti-Leu4/IL-2-mediated T cell proliferation. Thus, PMN potentiate T cell responsiveness to IL-2 in the presence of anti-CD3 mAb and this potentiation by PMN requires interaction of anti-CD3 with PMN-FcR.

Chronic acquired immunodeficiency syndrome-associated arthritis: a synovial ultrastructural study.

We describe a patient who developed acquired immunodeficiency syndrome-related complex, complicated by chronic, symmetric polyarthritis. Synovial biopsy showed large areas of plasma cell infiltration subjacent to the synovial lining. Ultrastructural study demonstrated tubuloreticular structures within endothelial cells, crystal-like inclusions in plasma cells, and virus-like particles located around synoviocyte fragments. Although immunologic and morphologic studies did not permit classification of these virus-like structures, the role of these possible virions in the pathogenesis of the observed synovitis remains to be determined. Surprisingly, the patient's chronic arthritis resolved with anti-retroviral treatment (azidothymidine: AZT).

Costs induced by hip fractures: a prospective controlled study in Belgium. Belgian Hip Fracture Study Group.

The economic burden of hip fractures is thought to be important, but the excess medical costs they induce remain largely unknown. We assessed the direct medical costs induced by hip fractures during and after hospitalization. Hospital costs of 170 consecutive Belgian women with hip fracture were gathered. During the year following discharge, all medical costs were collected for the 159 hip fracture women who survived the acute hospitalization stay. A similar collection of data was performed on a comparison group of 159 age-and residence-matched women without a history of hip fracture. The mean cost of the acute hospital stay was 8,667 Belgian francs and the mean 1-year hip-fracture-related extra costs after hospitalization was 6,636 Belgian francs. During the year following the acute hospital stay, 19% of the hip fracture women and 4% of the comparison women were newly admitted to nursing homes (p<0.001). Although health care costs increased with age, hip-fracture-related extra costs after hospitalization seemed similar in those below or above 81 years old. These extra costs amounted to 7,710 Belgian francs in women not living in nursing homes at the time of fracture, and to 3,479 Belgian francs in women who lived in nursing homes. Health or mental status before hip fracture seemed not to affect extra costs. Taking into account the higher mortality of women with hip fracture, the extra costs during the acute hospital stay and during the 1-year follow-up amounted to a mean 15,151 Belgian francs. In conclusion, both acute hospital stays and subsequent medical care contribute significantly to medical costs induced by hip fractures.

Relationship between magnetic resonance imaging and histologic findings by bone biopsy in nontraumatic osteonecrosis of the femoral head.

To attest the validity of magnetic resonance imaging (MRI) to evaluate the pathophysiology in nontraumatic osteonecrosis (ON) of the femoral head, we attempted to correlate the different MRI patterns with the histology in cases of early stages. We used not only the T1 and T2 pulse sequences, but also the T1 sequence after gadolinium-DTPA to demonstrate the presence of vascularization. Studying 24 core biopsies from 16 hips (9 patients), we explored the MRI presentations that corresponded to the main histologic findings of the different trabecular bone and bone marrow conditions. Histologic findings including trabecular bone necrosis and bone marrow necrosis represented by amorphous eosinophilic debris presented a low T1 signal intensity without enhancement after intravenous gadolinium injection and a low T2 signal intensity. Trabecular bone necrosis associated with mummified fat cells presented a normal T1 and T2 signal intensity. Trabecular bone necrosis with fibrosis filling the intertrabecular spaces had a low T1 signal intensity that was enhanced by gadolinium and had an intermediate T2 signal intensity. Bands of fibrosis without trabecular bone as seen in fracture zones showed a low T1 signal intensity that was enhanced by gadolinium with a high T2 signal intensity. Thickened trabecular bone with fibrosis as found in creeping substitution areas had also a low T1 signal enhanced by gadolinium, but the T2 signal intensity was low. Farther from the necrotic area, despite normal trabecular bone, we found some patchy necrosis of the bone marrow without any modification of the normal T1 and T2 MRI patterns.(ABSTRACT TRUNCATED AT 250 WORDS)

Structural and functional characteristics of the CD3 (T3) molecular complex on human thymocytes.

The CD3 (T3) molecular complex is noncovalently associated with the antigen receptor molecule on T cells. The mitogenic properties of anti-CD3 antibodies have suggested that this complex may be the transducer of the antigenic signal to the intracellular environment. In the present investigation, we studied some of the structural and functional characteristics of the CD3 complex on human thymocytes. In 11 specimens tested, we found that anti-CD3 antibodies react with 50 to 76% of the thymocytes. Two-color immunofluorescence analysis revealed that the majority (greater than 50%) of thymocytes express both CD3 and CD1 on their surfaces. The latter is a marker of immature thymocytes. However, a distinct subpopulation comprising 13 to 19% of the total cells displays only CD3, while an approximately equal percentage of cells expresses only CD1. The mitogenic potential of anti-CD3 antibodies on peripheral T cells is dependent on the presence of monocytes. Anti-CD3 antibodies by themselves cannot activate thymocytes, indicating that functionally active monocytes are absent from the thymocyte population. Even the addition of peripheral monocytes does not allow a response of thymocytes to anti-CD3 antibodies. However, when the anti-CD3 antibody 64.1 is added in the presence of exogenous rIL 2, a strong antibody and lymphokine dose-dependent response ensues. Only CD1- CD3+ thymocytes are stimulated by the addition of antibody and IL 2. The mere expression of CD3 on the CD1+ CD3+ subpopulation of thymocytes apparently is not sufficient to render the cells responsive to the signals of anti-CD3 and IL 2.