What have we learned from clinical trials in primary Sj?gren's syndrome about pathogenesis?

In vitro and in vivo experimental data have pointed to new immunopathogenic mechanisms in primary Sj?gren's syndrome (pSS). The availability of targeted treatment modalities has opened new ways to selectively target these mechanistic pathways in vivo. This has taught us that the role of proinflammatory cytokines, in particular TNFα, is not crucial in the immunopathogenesis of pSS. B cells appear to play a major role, as depletion of B cells leads to restoration of salivary flow and is efficacious for treatment of extraglandular manifestations and mucosa-associated lymphoid tissue lymphoma. B cells also orchestrate T-cell infiltration and ductal epithelial dearrangement in the salivary glands. Gene profiling of salivary gland tissue in relation to B-cell depletion confirms that the axis of IFNα, B-cell activating factor, B-cell activation, proliferation and survival constitutes a major pathogenic route in pSS.     

Ureide metabolism during seedling development in French bean (Phaseolus vulgaris)

French bean ( Phaseolus vulgaris ) is a legume that transports most of the atmospheric nitrogen fixed in its nodules to the aerial parts of the plant as ureides. Changes in ureide content and in enzymatic activities involved in their metabolism were identified in the cotyledons and embryonic axes during germination and early seedling development. Accumulation of ureides (ca. 1300 nmol per pair of cotyledons) was observed in the cotyledons of dry seeds. Throughout germination, the total amount of ureides slightly decreased to about 1200 nmol, but increased both in cotyledons and in embryonic axes after radicle emergence. In the axes, the ureides were almost equally distributed in roots, hypocotyls and epicotyls. The pattern of ureide distribution was not affected by the presence of nitrate or sucrose in the media up to 6 days after imbibition. Ureides are synthesized from purines because allopurinol (a xanthine dehydrogenase inhibitor) blocks the increase of ureides. Allantoin and allantoate-degrading activities were detected in French bean dried seeds, whereas no ureidoglycolate-degrading activity was detected. During germination, the levels of the three activities remain unchanged in cotyledons. After radicle emergence, the levels of activities in cotyledons changed. Allantoin-degrading activity increased, allantoate-degrading activity decreased and ureidoglycolate-degrading activity remained undetectable in cotyledons. In developing embryonic axes, the three activities were detected throughout germination and early seedling development. The embryonic axes are able to synthesize ureides, because those compounds accumulated in axes without cotyledons.     

Autophagy and NLRP3 inflammasome crosstalk in neuroinflammation in aged bovine brains

NLRP3 inflammasome is a multiprotein complex that can sense several stimuli such as autophagy dysregulation and increased reactive oxygen species production stimulating inflammation by priming the maturation of proinflammatory cytokines interleukin-1β and interleukin-18 in their active form. In the aging brain, these cytokines can mediate the innate immunity response priming microglial activation. Here, we describe the results of immunohistochemical and molecular analysis carried out on bovine brains. Our results support the hypothesis that the age-related impairment in cellular housekeeping mechanisms and the increased oxidative stress can trigger the inflammatory danger sensor NLRP3. Moreover, according to the recent scientific literature, we demonstrate the presence of an age-related proinflammatory environment in aged brains consisting in an upregulation of interleukin-1β, an increased microglial activation and increased NLRP3 expression. Finally, we suggest that bovine may potentially be a pivotal animal model for brain aging studies.     

The International Research Society of Spinal Deformities (IRSSD) and its contribution to science

From the time of its initial, informal meetings starting in 1980 to its formal creation in 1990, the IRSSD has met on a bi-annual basis to discuss all aspects of the spine and associated deformities. It has encouraged open discussion on all topics and, in particular, has tried to be the seed-bed for new ideas. The members are spread around the world and include people from all areas of academia as well as the most important people, the patients themselves. Most notably, application of the ideas and results of the research has always been at the forefront of the discussions. This paper was conceived with the idea of evaluating the impact made by the IRSSD over the last 30 years in the various areas and is intended to create discussion for the upcoming meeting in Montreal regarding future focus: " We are lost over the Atlantic Ocean but we are making good time."     

Impact of early applied upper limb stimulation: The EXPLICIT-stroke programme design

Background  

Main claims of the literature are that functional recovery of the paretic upper limb is mainly defined within the first month post stroke and that rehabilitation services should preferably be applied intensively and in a task-oriented way within this particular time window. EXplaining PLastICITy after stroke (acronym EXPLICIT-stroke) aims to explore the underlying mechanisms of post stroke upper limb recovery. Two randomized single blinded trials form the core of the programme, investigating the effects of early modified Constraint-Induced Movement Therapy (modified CIMT) and EMG-triggered Neuro-Muscular Stimulation (EMG-NMS) in patients with respectively a favourable or poor probability for recovery of dexterity.     

Vertebral rotation measurement: a summary and comparison of common radiographic and CT methods

Background

The conservative treatment of adolescent idiopathic scoliosis (AIS) has traditionally been divided into two phases–correction and stabilisation–and casts, even if less used today, can be considered the best standard in the correction phase. Till the present, however, no comparison between cast and brace efficacy has been proposed.

Methods

This is a prospective cohort study with a retrospective control group. The aim was to verify if it is possible to obtain with a specifically developed rigid brace results comparable to a cast. We considered fifty AIS patients who had refused surgery, aged 14.1 ± 1.5 years, with 46.7 ± 7.8° Cobb scoliosis. Thirty-two consecutive patients (with no drop-outs) were prospectively followed up with the Sforzesco brace (SBG), and compared against a retrospective group of eighteen patients treated with the Risser cast (RCG). The treatment time (the total correction phase) was 19 ± 3 months. Out-of-brace x-rays were compared, as well as clinical results.

Results

Compliance and hours of treatment were higher in the RCG while all the other parameters were not different. We observed a reduction of 6° Cobb and an important aesthetic gain in both groups (P<0.05). Three patients (6%) worsened, while 56% improved (36% at least 10°, and 14% 15° or more). The SBG did show results comparable to the RCG, with only minor differences in terms of scoliosis correction. On the contrary, straightening of the spine (decrease of the sagittal physiological curves) was much higher in the RCG but was not clinically significant in the SBG.

Conclusion

In the corrective phase of AIS treatment it is possible with a specific rigid brace (Sforzesco – SPoRT concept) to obtain scoliosis correction similar to cast. Due to the human and social costs of casting, and worst sagittal profile results, Sforzesco brace should be the preferred method wherever possible.     

Marked structural and functional heterogeneity in CXCR4: separation of HIV-1 and SDF-1alpha responses

CXCR4, the chemotactic cell receptor for SDF-1alpha, is essential for immune trafficking and HIV infection. CXCR4 is remarkably heterogeneous and the purpose of this study was to better identify the isoforms expressed by cells and compare their structure and function. We found that cells express either a predominant isoform or multiple isoforms. These were best resolved on SDS-PAGE using sucrose-gradient-fractionated, triton-insoluble, membrane extracts. We hypothesized that glycosyl modification may underpin some of this heterogeneity and that cell isoform(s) differences may underscore CXCR4's multiple cell functions. A comparison of wild-type (WT) and dual N-linked glycosylation site, N11A/N176A, mutant CXCR4 expressed in 3T3 and HEK-293 cells served to implicate variabilities in glycosylation and oligomerization in almost half of the isoforms. Immunoprecipitation of CXCR4 revealed monomer and dimer non-glycosylated forms of 34 kDa and 68 kDa from the N11A/N176A mutant, compared with glycosylated 40 kDa and 47 kDa and 73 kDa and 80 kDa forms from WT. The functional specificity of isoform action was also implicated because, despite CEMT4 cells expressing high levels of CXCR4 and 11 different isoforms, a single 83 kDa form was found to bind gp120 for HIV-1 IIIB infection. Furthermore, comparative studies found that in contrast to SDF-1alpha-responsive Nalm-6 cells that expressed similar levels of a single isoform, CEMT4 cells did not show a Ca(++) flux or a chemotactic response to SDF-1alpha. Thus, CXCR4 can differ both structurally and functionally between cells, with HIV-1 infection and chemotaxis apparently mediated by different isoforms. This separation of structure and function has implications for understanding HIV-1 entry and SDF-1alpha responses and may indicate therapeutic possibilities.     

Structural complexes in the squid giant axon membrane sensitive to ionic concentrations and cardiac glycosides

Giant nerve fibers of squid Sepioteuthis sepioidea were incubated for 10 min in artificial sea water (ASW) under control conditions, in the absence of various ions, and in the presence of cardiac glycosides. The nerve fibers were fixed in OsO4 and embedded in Epon, and structural complexes along the axolemma were studied.     

H-Type Bovine Spongiform Encephalopathy: Complex Molecular Features and Similarities with Human Prion Diseases

We previously reported that some cattle affected by bovine spongiform encephalopathy (BSE) showed distinct molecular features of the protease-resistant prion protein (PrP^res) in Western blot, with a 1–2 kDa higher apparent molecular mass of the unglycosylated PrP^res associated with labelling by antibodies against the 86–107 region of the bovine PrP protein (H-type BSE). By Western blot analyses of PrP^res, we now showed that the essential features initially described in cattle were observed with a panel of different antibodies and were maintained after transmission of the disease in C57Bl/6 mice. In addition, antibodies against the C-terminal region of PrP revealed a second, more C-terminally cleaved, form of PrP^res (PrP^res #2), which, in unglycosylated form, migrated as a ≈ 14 kDa fragment. Furthermore, a PrP^res fragment of ≈7 kDa, which was not labelled by C-terminus-specific antibodies and was thus presumed to be a product of cleavage at both N- and C-terminal sides of PrP protein, was also detected. Both PrP^res #2 and ≈7 kDa PrP^res were detected in cattle and in C57Bl/6 infected mice. These complex molecular features are reminiscent of findings reported in human prion diseases. This raises questions regarding the respective origins and pathogenic mechanisms in prion diseases of animals and humans.Key Words: prion, BSE, Creutzfeldt-Jakob, Gerstmann-Sträussler-Scheinker, Western blot, amyloid