HLA-DR in Brazilian patients with polyarteritis nodosa (PAN) and microscopic polyangiitis (MPA)

The aim of this study was to evaluate the frequency and clinical associations of HLA-DR alleles in Brazilian Caucasian patients with polyarteritis nodosa (PAN) or microscopic polyangiitis (MPA). We evaluated 29 Caucasian patients with vasculitis classified as PAN or MPA according to the American College of Rheumatology (ACR) 1990 Criteria, Chapel Hill Consensus Conference (CHCC) nomenclature for vasculitis and EULAR recommendations for conducting clinical studies in systemic vasculitis. HLA-DR alleles were typed using polymerase chain reaction-amplified DNA, hybridized with sequence-specific low resolution primers. DNA obtained from 59 Caucasian healthy blood donors were used as control. In order to evaluate if a specific HLA may have influence on the clinical profile of those diseases, we also divided the patients according to Birmingham vasculitis score (BVAS) and Five-Factors Score (FFS) at the time of diagnosis. Increased frequency of HLA-DRB1*16 (p = 0.023) and DRB4*01 (p = 0.048) was found in patients with higher disease activity at the time of diagnosis (BVAS >= 22). Patients with less severe disease (FFS = 0) had a higher frequency of HLA-DRB1*03 (p = 0.011). Patients with gastrointestinal tract involvement had significantly increased frequency of HLA-DRB1*11 or B1*12 (p = 0.046), B1*13 (p = 0.021) and B3 (p = 0.008). In contrast, patients with renal disease, had higher frequency of DRB1*15 or DRB1*16 (p = 0.035) and B5 (p = 0.035). In the subgroup of patients with MPA, increased frequency of HLA-DRB1*15 was found in patients with BVAS >= 22 (p = 0.038) and FFS >= 1 (p = 0.039) suggesting that this allele is associated with more aggressive disease. Antineutrophil cytoplasmic antibodies (ANCA) negative MPA patients had significantly increased frequency of HLA-DRB1*11 or DRB1*12 when compared to ANCA positive patients (p = 0.023). Our results suggest that HLA-DR alleles may influence PAN and MPA clinical expression and outcome and that in MPA they participate in the mechanisms involved in the development to ANCA.

Microscopic polyangiitis: Clinical presentation

Microscopic polyangiitis (MPA) is a member of the family of ANCA-associated vasculitides. Its characteristic histology shows a necrotizing small vessel vasculitis with little or absent immune deposits (pauci-immune vasculitis). In Western countries MPA shows a lower prevalence than Wegener's disease, it affects more men than women and commences at the age of > or = 50 years. The two organs most typically involved and often defining prognosis are the kidneys and the lungs. MPA may concomitantly or sequentially involve other organs such as the nervous system, the skin, the musculoskeletal system, but also the heart, the eye and the intestines. Treatment decisions should be based on severity and pattern of organ involvement and respect the five factor score (FFS). Life- or organ- threatening disease is treated with glucocorticoids and (pulse) cyclophosphamide. Plasmapheresis and i.v.immunoglobulins have been shown to be beneficial as additional measure in severe cases. If renal function is preserved, Methotrexate may be considered to induce remission, and if the FFS equals 0, remission may be induced with glucocorticoid monotherapy. Maintenance therapy is recommended with Azathioprin, mycophenolate mofetil may be used as a second line drug. Biologic agents such as monoclonal antibodies to tumor necrosis factor a and B cell depleting rituximab have been shown to bear remission-inducing quality.

Utilizzo del Rituximab nel trattamento della vasculiti ANCA associate.

Introduzione. Recenti studi hanno dimostrato che il Rituximab (RTX) è un’alternativa sicura ed efficace alla ciclofosfamide nell’indurre la remissione in pazienti con severa vasculite ANCA-associata (AAV) di nuova diagnosi o recidiva. Scopo dello studio era valutare l’efficacia e la sicurezza del RTX nei nostri pazienti con AAV. Metodi. Studio retrospettivo delle caratteristiche cliniche, dei risultati e della tolleranza al RTX dei pazienti con AAV trattati presso il nostro centro da Gennaio 2006 a Dicembre 2011. Inizialmente veniva utilizzato lo schema convenzionale delle 4 somministrazioni settimanali da 375 mg/m2. Dal 2011 sulla base dell’esperienza maturata e dei nuovi dati della letteratura si decideva di non adottare uno schema fisso per le recidive, ma di somministrare una o due dosi secondo la severità della recidiva ed il rischio infettivo. Risultati. Venivano trattati 51 pazienti con AAV, 15/51 (29%) di nuova diagnosi e 36/51 (71%) ad una recidiva. La maggior parte dei pazienti con nuova diagnosi presentavano una micropoliangioite con severo interessamento renale, 5/15 (33%) erano in dialisi dall’esordio. 32/36 (89%) pazienti trattati ad una recidiva presentavano una recidiva granulomatosa di Granulomatosi di Wegener (WG). Tutti ottenevano una remissione, più rapidamente per le manifestazioni vasculitiche. 2/5 pazienti in dialisi dall’esordio recuperavano la funzione renale. Si osservavano 11 recidive in 9 pazienti con GW mediamente dopo 23.1 mesi, tutti ottenevano nuovamente la remissione. Ad un follow-up medio di 20.1 mesi si registravano 4 decessi, 3 (3/15, 20%) nel gruppo di pazienti con nuova diagnosi, uno (1/36, 3%) nel gruppo trattato ad una recidiva. Quattro pazienti sospendevano il RTX per infezioni. Conclusioni. Nella nostra casistica il RTX si è dimostrato efficace e sicuro nell’indurre la remissione in pazienti con severa AAV, sia all’esordio che alla recidiva. I pazienti con WG presentano maggior rischio di recidiva e dovrebbero pertanto essere mantenuti in terapia immunosoppressiva dopo RTX.

Vasculitides associated with IgG antineutrophil cytoplasmic autoantibodies in childhood

Immunoglobulin (Ig)G antineutrophil cytoplasmic autoantibodies are causally associated with necrotizing vasculitides that are characterized immunopathologically by little or no deposition of immunoreactants, such as Wegener granulomatosis, microscopic polyangiitis, Churg-Strauss angiitis, "renal-limited" vasculitis and a number of drug-induced vasculitides. Clinical routine testing targets the antigens myeloperoxidase and proteinase 3. However, in all of the conditions mentioned, the renal histopathologic findings are indistinguishable. Churg-Strauss angiitis (characterized by necrotizing vasculitis, granulomatous inflammation and tissue eosinophilia), Wegener granulomatosis (characterized by necrotizing vasculitis and granulomatous inflammation) and microscopic polyangiitis (characterized by necrotizing vasculitis) often present with fever, weight loss and a multisystem involvement (ear, nose, throat, lung, eyes, peripheral nerve and heart). Fifty years ago these conditions were very often fatal within 6 months of diagnosis. The introduction of corticosteroids and cyclophosphamide has resulted in a dramatic clinical benefit. Patients who develop treatment-related morbidity can be switched from cyclophosphamide to azathioprine after achieving remission. In patients with less severe disease, methotrexate achieves remission with a success rate similar to that of cyclophosphamide. Plasma exchange, in association with immunosuppression, is likely to be a beneficial therapy for patients with severe kidney disease or pulmonary hemorrhage.

[Systemic ANCA-associated vasculitis--diagnosis and therapy]

ANCA-associated vasculitis represents a group of small-vessel vasculitides, including Wegener's granulomatosis, microscopic polyangiitis and the Churg-Strauss-syndrome. These diseases affect mainly small arteries, venules and capillaries, showing a lack of immunocomplex formation on immunohistology, the so-called "pauci-immune" vasculitis. Nevertheless, Anti-Neutrophil Cytoplasmatic Autoantibodies (ANCA's) are pathogenic for this type of disease. In spite of important advances in technical diagnostic tools, careful medical history and clinical examinations often give the clues for the correct diagnosis. Recent collaborative therapeutic studies have lead to therapeutic schemas that are much more adapted to the individual disease state. Besides the acute and sometimes life-threatening form of ANCA-vasculitis, chronic disease and relapses become more important in clinical practice. Thus, therapeutic efficacy must be outweighed against long-term toxicity to make the right choice for therapeutic intervention in ANCA-associated vasculitis.

Pulmonary renal syndrome in childhood: a report of twenty-one cases and a review of the literature

In adults, the term specific pulmonary renal syndrome describes disorders with pulmonary and glomerular manifestations and includes Wegener's granulomatosis, Goodpasture disease, and systemic lupus erythematosus. Nonspecific pulmonary renal syndrome refers to either pulmonary disease complicating glomerular disease, or glomerular diseases following pulmonary disease. Since little is known regarding pulmonary renal syndrome in childhood, we reviewed the charts of 21 pediatric patients with pulmonary renal syndromes treated by the Department of Pediatrics, University of Bern between 1991 and 1998; we also reviewed the pediatric literature that deals with specific pulmonary renal syndromes. Specific pulmonary renal syndrome was noted in 3 children with systemic vasculitis (Wegener granulomatosis, N = 2; microscopic polyangiitis, N = 1) and 2 with systemic lupus erythematosus. Nonspecific pulmonary renal syndrome was observed in 12 patients with pulmonary edema (N = 9), pulmonary thromboembolism (N = 2), and pulmonary infection (N = 1) complicating the course of a glomerular disease, and in 4 children with a pulmonary disease followed by a glomerular disease. Review of the literature disclosed 52 cases of specific pulmonary renal syndrome other than systemic lupus erythematosus: Wegener granulomatosis (N = 28), Goodpasture disease (N = 13), and Henoch-Schönlein purpura (N = 11). In addition, hemolytic uremic syndrome complicated pneumococcal pneumonia in 32 cases. We conclude that pulmonary renal syndromes need to be looked for in childhood. Apart from Wegener granulomatosis, Goodpasture disease, and systemic lupus erythematosus, Henoch-Schönlein purpura and hemolytic-uremic syndrome occasionally have both pulmonary and renal features.

Raman microscopic study of the Li amphibole holmquistite, from the Martin Marietta Quarry, Bessemer City, NC, USA

The Raman spectrum of holmquistite, a Li-containing orthorhombic amphibole from Bessemer City, USA has been measured. The OH-stretching region is characterized by bands at 3661, 3646, 3634 and 3614 cm–1 assigned to 3 Mg–OH, 2 Mg + Fe2+–OH, Mg + 2Fe2+–OH and 3 Fe2+–OH, respectively. These Mg and Fe2+ cations are located at the M1 and M3 sites and have a Fe2+/(Fe2+ + Mg) ratio of 0.35. The 960–1110 cm–1 region represents the antisymmetric Si–O–Si and O–Si–O stretching vibrations. For holmquistite, strong bands are observed around 1022 and 1085 cm–1 with a shoulder at 1127 cm–1 and minor bands at 1045 and 1102 cm–1. In the region 650–800 cm–1 bands are observed at 679, 753 and 791 cm–1 with a minor band around 694 cm–1 attributed to the symmetrical Si–O–Si and Si–O vibrations. The region below 625 cm–1 is characterized by 14 vibrations related to the deformation modes of the silicate double chain and vibrations involving Mg, Fe, Al and Li in the various M sites. The 502 cm–1 band is a Li–O deformation mode while the 456, 551 and 565 cm–1 bands are Al–O deformation modes.

Microscopic modelling of freeway operations

Freeways are divided roadways designed to facilitate the uninterrupted movement of motor vehicles. However, many freeways now experience demand flows in excess of capacity, leading to recurrent congestion. The Highway Capacity Manual (TRB, 1994) uses empirical macroscopic relationships between speed, flow and density to quantify freeway operations and performance. Capacity may be predicted as the maximum uncongested flow achievable. Although they are effective tools for design and analysis, macroscopic models lack an understanding of the nature of processes taking place in the system. Szwed and Smith (1972, 1974) and Makigami and Matsuo (1990) have shown that microscopic modelling is also applicable to freeway operations. Such models facilitate an understanding of the processes whilst providing for the assessment of performance, through measures of capacity and delay. However, these models are limited to only a few circumstances. The aim of this study was to produce more comprehensive and practical microscopic models. These models were required to accurately portray the mechanisms of freeway operations at the specific locations under consideration. The models needed to be able to be calibrated using data acquired at these locations. The output of the models needed to be able to be validated with data acquired at these sites. Therefore, the outputs should be truly descriptive of the performance of the facility. A theoretical basis needed to underlie the form of these models, rather than empiricism, which is the case for the macroscopic models currently used. And the models needed to be adaptable to variable operating conditions, so that they may be applied, where possible, to other similar systems and facilities. It was not possible to produce a stand-alone model which is applicable to all facilities and locations, in this single study, however the scene has been set for the application of the models to a much broader range of operating conditions. Opportunities for further development of the models were identified, and procedures provided for the calibration and validation of the models to a wide range of conditions. The models developed, do however, have limitations in their applicability. Only uncongested operations were studied and represented. Driver behaviour in Brisbane was applied to the models. Different mechanisms are likely in other locations due to variability in road rules and driving cultures. Not all manoeuvres evident were modelled. Some unusual manoeuvres were considered unwarranted to model. However the models developed contain the principal processes of freeway operations, merging and lane changing. Gap acceptance theory was applied to these critical operations to assess freeway performance. Gap acceptance theory was found to be applicable to merging, however the major stream, the kerb lane traffic, exercises only a limited priority over the minor stream, the on-ramp traffic. Theory was established to account for this activity. Kerb lane drivers were also found to change to the median lane where possible, to assist coincident mergers. The net limited priority model accounts for this by predicting a reduced major stream flow rate, which excludes lane changers. Cowan's M3 model as calibrated for both streams. On-ramp and total upstream flow are required as input. Relationships between proportion of headways greater than 1 s and flow differed for on-ramps where traffic leaves signalised intersections and unsignalised intersections. Constant departure onramp metering was also modelled. Minimum follow-on times of 1 to 1.2 s were calibrated. Critical gaps were shown to lie between the minimum follow-on time, and the sum of the minimum follow-on time and the 1 s minimum headway. Limited priority capacity and other boundary relationships were established by Troutbeck (1995). The minimum average minor stream delay and corresponding proportion of drivers delayed were quantified theoretically in this study. A simulation model was constructed to predict intermediate minor and major stream delays across all minor and major stream flows. Pseudo-empirical relationships were established to predict average delays. Major stream average delays are limited to 0.5 s, insignificant compared with minor stream delay, which reach infinity at capacity. Minor stream delays were shown to be less when unsignalised intersections are located upstream of on-ramps than signalised intersections, and less still when ramp metering is installed. Smaller delays correspond to improved merge area performance. A more tangible performance measure, the distribution of distances required to merge, was established by including design speeds. This distribution can be measured to validate the model. Merging probabilities can be predicted for given taper lengths, a most useful performance measure. This model was also shown to be applicable to lane changing. Tolerable limits to merging probabilities require calibration. From these, practical capacities can be estimated. Further calibration is required of traffic inputs, critical gap and minimum follow-on time, for both merging and lane changing. A general relationship to predict proportion of drivers delayed requires development. These models can then be used to complement existing macroscopic models to assess performance, and provide further insight into the nature of operations.

Freeway traffic oscillations : microscopic analysis of formations and propagations using Wavelet Transform

In this paper we identify the origins of stop-and-go (or slow-and-go) driving and measure microscopic features of their propagations by analyzing vehicle trajectories via Wavelet Transform. Based on 53 oscillation cases analyzed, we find that oscillations can be originated by either lane-changing maneuvers (LCMs) or car-following behavior (CF). LCMs were predominantly responsible for oscillation formations in the absence of considerable horizontal or vertical curves, whereas oscillations formed spontaneously near roadside work on an uphill segment. Regardless of the trigger, the features of oscillation propagations were similar in terms of propagation speed, oscillation duration, and amplitude. All observed cases initially exhibited a precursor phase, in which slow-and-go motions were localized. Some of them eventually transitioned into a well developed phase, in which oscillations propagated upstream in queue. LCMs were primarily responsible for the transition, although some transitions occurred without LCMs. Our findings also suggest that an oscillation has a regressive effect on car following behavior: a deceleration wave of an oscillation affects a timid driver (with larger response time and minimum spacing) to become less timid and an aggressive driver less aggressive, although this change may be short-lived. An extended framework of Newell’s CF is able to describe the regressive effects with two additional parameters with reasonable accuracy, as verified using vehicle trajectory data.

Microscopic and spectroscopic investigation of poly(3-hexylthiophene) interaction with carbon nanotubes

The inclusion of carbon nanotubes in polymer matrix has been proposed to enhance the polymer’s physical and electrical properties. In this study, microscopic and spectroscopic techniques are used to investigate the interaction between poly(3-hexylthiophene) (P3HT) and nanotubes and the reciprocal modification of physical properties. The presence of P3HT-covered nanotubes dispersed in the polymer matrix has been observed by atomic force microscopy and transmission electron microscopy. Then, the modification of P3HT optical properties due to nanotube inclusion has been evidenced with spectroscopic techniques like absorption and Raman spectroscopy. The study is completed with detailed nanoscale analysis by scanning probe techniques. The ordered self assembly of polymer adhering on the nanotube is unveiled by showing an example of helical wrapping of P3HT. Scanning tunneling spectroscopy study provides information on the electronic structure of nanotube-polymer assembly, revealing the charge transfer from P3HT to the nanotube.

Issues and concerns of microscopic calibration process at different network levels : case study of Pacific Motorway

Calibration process in micro-simulation is an extremely complicated phenomenon. The difficulties are more prevalent if the process encompasses fitting aggregate and disaggregate parameters e.g. travel time and headway. The current practice in calibration is more at aggregate level, for example travel time comparison. Such practices are popular to assess network performance. Though these applications are significant there is another stream of micro-simulated calibration, at disaggregate level. This study will focus on such microcalibration exercise-key to better comprehend motorway traffic risk level, management of variable speed limit (VSL) and ramp metering (RM) techniques. Selected section of Pacific Motorway in Brisbane will be used as a case study. The discussion will primarily incorporate the critical issues encountered during parameter adjustment exercise (e.g. vehicular, driving behaviour) with reference to key traffic performance indicators like speed, lane distribution and headway; at specific motorway points. The endeavour is to highlight the utility and implications of such disaggregate level simulation for improved traffic prediction studies. The aspects of calibrating for points in comparison to that for whole of the network will also be briefly addressed to examine the critical issues such as the suitability of local calibration at global scale. The paper will be of interest to transport professionals in Australia/New Zealand where micro-simulation in particular at point level, is still comparatively a less explored territory in motorway management.