White matter microstructural alterations in migraine: a diffusion-weighted MRI study

Migraine is a common and disabling neurological disease. The pathomechanism that underlies the disorder is not entirely understood, and reliable biomarkers are missing. In the current analysis we looked for microstructural alterations of the brain white matter in migraine patients by means of diffusion-weighted magnetic resonance imaging. The measurements were carried out with a novel approach based on fine-tuned nonlinear registration and nonparametric permutation test in an alignment-invariant tract representation (Tract-Based Spatial Statistics). We found reduced fractional anisotropy in the right frontal white matter cluster of migraine patients. In the same region we also found increased mean diffusivity and increased radial diffusivity. The probabilistic tractography showed connection of this cluster to other parts of the pain network (orbitofrontal cortex, insula, thalamus, dorsal midbrain). We speculate that these findings reflect maladaptive plastic changes or white matter disintegration.     

Real time decision support system for diagnosis of rare cancers, trained in parallel, on a graphics processing unit

In the present study a new strategy is introduced for designing and developing of an efficient dynamic Decision Support System (DSS) for supporting rare cancers decision making. The proposed DSS operates on a Graphics Processing Unit (GPU) and it is capable of adjusting its design in real time based on user-defined clinical questions in contrast to standard CPU implementations that are limited by processing and memory constrains. The core of the proposed DSS was a Probabilistic Neural Network classifier and was evaluated on 140 rare brain cancer cases, regarding its ability to predict tumors' malignancy, using a panel of 20 morphological and textural features Generalization was estimated using an external 10-fold cross-validation. The proposed GPU-based DSS achieved significantly higher training speed, outperforming the CPU-based system by a factor that ranged from 267 to 288 times. System design was optimized using a combination of 4 textural and morphological features with 78.6% overall accuracy, whereas system generalization was 73.8%±3.2%. By exploiting the inherently parallel architecture of a consumer level GPU, the proposed approach enables real time, optimal design of a DSS for any user-defined clinical question for improving diagnostic assessments, prognostic relevance and concordance rates for rare cancers in clinical practice.     

Comparative effectiveness and survival of infliximab,adalimumab, and etanercept for rheumatoid arthritis patients in the Hellenic Registry of Biologics: Low rates of remission and 5-year drug survival

Objective

To compare effectiveness, drug survival, and safety between infliximab, adalimumab, and etanercept, in a nationwide cohort of rheumatoid arthritis (RA) patients.

Methods

This study is a prospective cohort study of 1208 active RA patients. Effectiveness, drug survival, and serious adverse events during entire follow-up (median 2.9 years) were monitored.

Results

EULAR and CDAI responses were comparable between the three agents (EULAR good/moderate responses at 12 months ranged 76–79%). At 12 months, 15–23% achieved remission. For adalimumab and etanercept, adjusted hazard rate (HR) for EULAR/ACR remission (reference: infliximab) was 2.7 and 2.1 (95% confidence interval was 1.7–4.1 and 1.3–3.4, respectively); males (HR 1.6; 1.1–2.4), use of glucocorticoids (HR 2.0; 1.3–3.0), and swollen joint count >7 (HR 0.36; 0.24–0.55) were independent predictors. Five-year drug survival was 31%, 43%, and 49% for infliximab, adalimumab, and etanercept, respectively (p = 0.010). Infliximab was associated with significantly more withdrawals due to adverse events. Disease activity, CRP, and use of glucocorticoids predicted efficacy-related drug survival; age, use of methotrexate, and prior DMARDs failures predicted safety-related survival. Risk for serious infections was lower with adalimumab (odds ratio [OR] 0.62; 0.38–1.00) or etanercept (OR 0.39; 0.21–0.72) than infliximab, independent of the effects of age (OR 1.65; 1.37–2.00 per 10 years), tender joint count >10 (OR 1.86; 1.21–2.86), and glucocorticoids >35 mg/week (OR 1.83; 1.12–2.99).

Conclusions

Response rates were comparable among anti-TNF agents. Overall, 5-year drug survival was below 50%, with infliximab demonstrating increased safety-related discontinuations. Remission rates are low in clinical practice. Strategies to increase effectiveness and long-term survival of anti-TNF agents in RA are needed.     

Elimination of bacteria on different implant surfaces through photosensitization and soft laser. An in vitro study.

Microbiologic examinations of implants have shown that certain micro‐organisms described as periodontal pathogens may have an influence on the development and the progression of peri‐implant disease. This experimental study aimed to examine the bactericidal effect of irradiation with a soft laser on bacteria associated with peri‐implantitis following exposure to a photo‐sensitizing substance. Platelets made of commercially pure titanium, either with a machined surface or with a hydroxyapatite or plasma‐flame‐sprayed surface or with a corundum‐blasted and etched surface, were incubated with a pure suspension of Actinobacillus actinomyetemcomitans or Porphyromonas gingivalis or Prevotella intermedia. The surfaces were then treated with a toluidine blue solution and irradiated with a diode soft laser with a wave length of 905 nm for 1 min. None of the smears obtained from the thus treated surfaces showed bacterial growth, whereas the smears obtained from surfaces that had been subjected to only one type of treatment showed unchanged growth of every target organism tested ( P <0.0006). Electron microscopic inspection of the thus treated platelets revealed that combined dye/laser treatment resulted in the destruction of bacterial cells. The present in vitro results indicate that lethal photosensitization may be of use for treatment of peri‐implantitis.     

A novel missense mutation of the CYLD gene identified in a Hungarian family with Brooke–Spiegler syndrome

Brooke–Spiegler syndrome (BSS; OMIM 605041) is an autosomal dominant disease characterized by skin appendage tumors due to mutations in the cylindromatosis gene (CYLD). We investigated a Hungarian BSS pedigree with two affected members, father and daughter. Direct sequencing demonstrated a novel missense mutation (c.2613C>G; p.His871Gln) in exon 19 within the ubiquitin‐specific protease domain of the encoded protein. We performed preliminary analysis to reveal the functional role of this novel mutation. Our data suggest that this novel CYLD mutation leads to increased ubiquitination of NEMO through influencing deubiquitinating activity of the CYLD protein and thus may result in enhanced NF‐κB signalling.     

Na+ regulation of formyl peptide receptor-mediated signal transduction in HL 60 cells. Evidence that the cation prevents activation of the G-protein by unoccupied receptors

In neutrophils and several other phagocytes, a pertussis and cholera toxin-sensitive guanine nucleotide-binding protein (G-protein) couples the receptors for formyl methionine-containing chemotactic peptides to stimulation of phospholipase C. We used membranes of myeloid-differentiated HL 60 cells to study the role of Na+ in regulating both the interaction of the formyl peptide receptor with the chemotactic agonist, N-formyl-methionyl-leucyl-phenylalanine (FMLP), and the receptor-mediated activation of the G-protein. Monovalent cations (Na+ greater than Li+ greater than K+ greater than choline+) markedly inhibited the binding of the radiolabeled oligopeptide [3H]FMLP by specifically reducing the number of receptors in the high-affinity state. Half-maximal and maximal inhibition of peptide binding were seen at cation concentrations of approximately 20 and 200 mM, respectively. Inhibition of peptide binding by Na+ was observed in the presence and absence of divalent cations and was strictly additive to inhibition by the poorly hydrolyzable GTP analogue, guanosine-5'-O-(3-thiotriphosphate), or to ADP ribosylation of G-proteins by pertussis toxin. The inhibitory effect of Na+ on peptide binding coincided with a marked reduction of the potency of FMLP to stimulate a high-affinity GTPase. In contrast, the degree of FMLP-stimulated GTPase activity was markedly enhanced in the presence of Na+. This was largely due to the fact that Na+ reduced the agonist-independent basal GTPase activity in the same way but less so than pertussis toxin treatment. The results show that monovalent cations, Na+ in particular, regulate the interaction of the formyl peptide receptor with both the chemotactic agonist and the G-protein by acting on a single site, possibly located on the receptor itself. The observation that basal GTPase activity is markedly reduced by both Na+ and pertussis toxin treatment also suggests (a) that G-proteins interact with and are activated by receptors even in the absence of agonists and (b) that Na+ uncouples unoccupied receptors from G-protein interaction and activation.