Guillain-Barré syndrome: a century of progress

In 1916, Guillain, Barré and Strohl reported on two cases of acute flaccid paralysis with high cerebrospinal fluid protein levels and normal cell counts — novel findings that identified the disease we now know as Guillain–Barré syndrome (GBS). 100 years on, we have made great progress with the clinical and pathological characterization of GBS. Early clinicopathological and animal studies indicated that GBS was an immune-mediated demyelinating disorder, and that severe GBS could result in secondary axonal injury; the current treatments of plasma exchange and intravenous immunoglobulin, which were developed in the 1980s, are based on this premise. Subsequent work has, however, shown that primary axonal injury can be the underlying disease. The association of Campylobacter jejuni strains has led to confirmation that anti-ganglioside antibodies are pathogenic and that axonal GBS involves an antibody and complement-mediated disruption of nodes of Ranvier, neuromuscular junctions and other neuronal and glial membranes. Now, ongoing clinical trials of the complement inhibitor eculizumab are the first targeted immunotherapy in GBS

Novel AlkB Dioxygenases—Alternative Models for In Silico and In Vivo Studies

Background: ALKBH proteins, the homologs of Escherichia coli AlkB dioxygenase, constitute a direct, single-protein repair system, protecting cellular DNA and RNA against the cytotoxic and mutagenic activity of alkylating agents, chemicals significantly contributing to tumor formation and used in cancer therapy. In silico analysis and in vivo studies have shown the existence of AlkB homologs in almost all organisms. Nine AlkB homologs (ALKBH1–8 and FTO) have been identified in humans. High ALKBH levels have been found to encourage tumor development, questioning the use of alkylating agents in chemotherapy. The aim of this work was to assign biological significance to multiple AlkB homologs by characterizing their activity in the repair of nucleic acids in prokaryotes and their subcellular localization in eukaryotes. Methodology and Findings: Bioinformatic analysis of protein sequence databases identified 1943 AlkB sequences with eight new AlkB subfamilies. Since Cyanobacteria and Arabidopsis thaliana contain multiple AlkB homologs, they were selected as model organisms for in vivo research. Using E. coli alkB2 mutant and plasmids expressing cyanobacterial AlkBs, we studied the repair of methyl methanesulfonate (MMS) and chloroacetaldehyde (CAA) induced lesions in ssDNA, ssRNA, and genomic DNA. On the basis of GFP fusions, we investigated the subcellular localization of ALKBHs in A. thaliana and established its mostly nucleo-cytoplasmic distribution. Some of the ALKBH proteins were found to change their localization upon MMS treatment. Conclusions: Our in vivo studies showed highly specific activity of cyanobacterial AlkB proteins towards lesions and nucleic acid type. Subcellular localization and translocation of ALKBHs in A. thaliana indicates a possible role for these proteins in the repair of alkyl lesions. We hypothesize that the multiplicity of ALKBHs is due to their involvement in the metabolism of nucleo-protein complexes; we find their repair by ALKBH proteins to be economical and effective alternative to degradation and de novo synthesis

Distinct gene subsets in pterygia formation and recurrence: dissecting complex biological phenomenon using genome wide expression data

<p>Abstract</p> <p>Background</p> <p>Pterygium is a common ocular surface disease characterized by fibrovascular invasion of the cornea and is sight-threatening due to astigmatism, tear film disturbance, or occlusion of the visual axis. However, the mechanisms for formation and post-surgical recurrence of pterygium are not understood, and a valid animal model does not exist. Here, we investigated the possible mechanisms of pterygium pathogenesis and recurrence.</p> <p>Methods</p> <p>First we performed a genome wide expression analysis (human Affymetrix Genechip, >22000 genes) with principal component analysis and clustering techniques, and validated expression of key molecules with PCR. The controls for this study were the un-involved conjunctival tissue of the same eye obtained during the surgical resection of the lesions. Interesting molecules were further investigated with immunohistochemistry, Western blots, and comparison with tear proteins from pterygium patients.</p> <p>Results</p> <p>Principal component analysis in pterygium indicated a signature of matrix-related structural proteins, including fibronectin-1 (both splice-forms), collagen-1A2, keratin-12 and small proline rich protein-1. Immunofluorescence showed strong expression of keratin-6A in all layers, especially the superficial layers, of pterygium epithelium, but absent in the control, with up-regulation and nuclear accumulation of the cell adhesion molecule CD24 in the pterygium epithelium. Western blot shows increased protein expression of beta-microseminoprotein, a protein up-regulated in human cutaneous squamous cell carcinoma. Gene products of 22 up-regulated genes in pterygium have also been found by us in human tears using nano-electrospray-liquid chromatography/mass spectrometry after pterygium surgery. Recurrent disease was associated with up-regulation of sialophorin, a negative regulator of cell adhesion, and <it>never in mitosis a</it>-5, known to be involved in cell motility.</p> <p>Conclusion</p> <p>Aberrant wound healing is therefore a key process in this disease, and strategies in wound remodeling may be appropriate in halting pterygium or its recurrence. For patients demonstrating a profile of 'recurrence', it may be necessary to manage as a poorer prognostic case and perhaps, more adjunctive treatment after resection of the primary lesion.</p

Comparative phylogeography of capitulate Campanula species from the Balkans, with description of a new species, C. daucoides

Capitulate inflorescence is a specific, strongly adaptive and rare feature in the genus Campanula. We studied morphologically eight capitulate Campanula taxa from the Balkans (1537 individuals/52 populations) and one more species from Caucasus at the molecular level (using chloroplast markers trnG(UCC)-trnS(GCU) and psbA-trnH, 130 individuals/58 populations) to assess their relations and evolutionary histories. Although all studied taxa were well circumscribed at both the morphological and molecular levels (except morphologically distinct but genetically invariable C. moesiaca which acquired its single haplotype via past cytoplasmic introgression from C. cervicaria), their relations inferred from the two datasets were incongruent possibly due to the homoplasy of morphological characters frequently reported in Campanula. Interspecific hybridization and introgression affected majority of studied species and may be more common in Campanula than previously thought. These processes, along with incomplete lineage sorting and retention of ancestral polymorphisms, hampered our phylogenetic reconstructions and prevented us to fully resolve species relations, and to support monophyletic origin of capitulate Campanula species. Nonetheless, several cryptic taxa were delineated, and C. daucoides was described as a new capitulate Campanula species. Different evolutionary histories and multiple glacial refugia were inferred for all species represented by multiple samples (except C. moesiaca). According to our dating, their speciation was in most cases triggered by various geo-historic events such as the uplift of the Alpide belt, Messinian Salinity Crisis, or desiccation of the Pannonian Sea/Pliocene Lakes from the central Balkans, while their further diversification was mainly driven by the onset of the Quaternary and cycles of glacials/interglacials

Strategy for the management of complex retinal detachments: the European vitreo-retinal society retinal detachment study report 2

OBJECTIVE: To study the outcome of the treatment of complex rhegmatogenous retinal detachments (RRDs). DESIGN: Nonrandomized, multicenter, retrospective study. PARTICIPANTS: One hundred seventy-six surgeons from 48 countries spanning 5 continents reported primary procedures for 7678 RRDs. METHODS: Reported data included clinical manifestations, the method of repair, and the outcome. MAIN OUTCOME MEASURES: Failure of retinal detachment repair (level 1 failure rate), remaining silicone oil at the study's conclusion (level 2 failure rate), and need for additional procedures to repair the detachments (level 3 failure rate). RESULTS: The main categories of complex retinal detachments evaluated in this investigation were: (1) grade B proliferative vitreoretinopathy (PVR; n = 917), (2) grade C-1 PVR (n = 637), (3) choroidal detachment or significant hypotony (n = 578), (4) large or giant retinal tears (n = 1167), and (5) macular holes (n = 153). In grade B PVR, the level 1 failure rate was higher when treated with a scleral buckle alone versus vitrectomy (P = 0.0017). In grade C-1 PVR, there was no statistically significant difference in the level 1 failure rate between those treated with vitrectomy, with or without scleral buckle, and those treated with scleral buckle alone (P = 0.7). Vitrectomy with a supplemental buckle had an increased failure rate compared with those who did not receive a buckle (P = 0.007). There was no statistically significant difference in level 1 failure rate between tamponade with gas versus silicone oil in patients with grade B or C-1 PVR. Cases with choroidal detachment or hypotony treated with vitrectomy had a significantly lower failure rate versus treatment with scleral buckle alone (P = 0.0015). Large or giant retinal tears treated with vitrectomy also had a significantly lower failure rate versus treatment with scleral buckle (P = 7×10(-8)). CONCLUSIONS: In patients with retinal detachment, when choroidal detachment, hypotony, a large tear, or a giant tear is present, vitrectomy is the procedure of choice. In retinal detachments with PVR, tamponade with either gas or silicone oil can be considered. If a vitrectomy is to be performed, these data suggest that a supplemental buckle may not be helpful. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article

Strategy for the management of uncomplicated retinal detachments: the European vitreo-retinal society retinal detachment study report 1

OBJECTIVE: To study success and failure in the treatment of uncomplicated rhegmatogenous retinal detachments (RRDs). DESIGN: Nonrandomized, multicenter retrospective study. PARTICIPANTS: One hundred seventy-six surgeons from 48 countries spanning 5 continents provided information on the primary procedures for 7678 cases of RRDs including 4179 patients with uncomplicated RRDs. METHODS: Reported data included specific clinical findings, the method of repair, and the outcome after intervention. MAIN OUTCOME MEASURES: Final failure of retinal detachment repair (level 1 failure rate), remaining silicone oil at the study's conclusion (level 2 failure rate), and need for additional procedures to repair the detachment (level 3 failure rate). RESULTS: Four thousand one hundred seventy-nine uncomplicated cases of RRD were included. Combining phakic, pseudophakic, and aphakic groups, those treated with scleral buckle alone (n = 1341) had a significantly lower final failure rate than those treated with vitrectomy, with or without a supplemental buckle (n = 2723; P = 0.04). In phakic patients, final failure rate was lower in the scleral buckle group compared with those who had vitrectomy, with or without a supplemental buckle (P = 0.028). In pseudophakic patients, the failure rate of the initial procedure was lower in the vitrectomy group compared with the scleral buckle group (P = 3×10(-8)). There was no statistically significant difference in failure rate between segmental (n = 721) and encircling (n = 351) buckles (P = 0.5). Those who underwent vitrectomy with a supplemental scleral buckle (n = 488) had an increased failure rate compared with those who underwent vitrectomy alone (n = 2235; P = 0.048). Pneumatic retinopexy was found to be comparable with scleral buckle when a retinal hole was present (P = 0.65), but not in cases with a flap tear (P = 0.034). CONCLUSIONS: In the treatment of uncomplicated phakic retinal detachments, repair using scleral buckle may be a good option. There was no significant difference between segmental versus 360-degree buckle. For pseudophakic uncomplicated retinal detachments, the surgeon should balance the risks and benefits of vitrectomy versus scleral buckle and keep in mind that the single-surgery reattachment rate may be higher with vitrectomy. However, if a vitrectomy is to be performed, these data suggest that a supplemental buckle is not helpful