Tocilizumab for the Treatment of Mevalonate Kinase Deficiency

Mevalonate kinase deficiency (MKD) is a severe autoinflammatory disease caused by recessive mutations in MVK resulting in reduced function of the enzyme mevalonate kinase, involved in the cholesterol/isoprenoid pathway. MKD presents with periodic episodes of severe systemic inflammation, poor quality of life, and life-threatening sequelae if inadequately treated. We report the case of a 12-year-old girl with MKD and severe autoinflammation that was resistant to IL-1 and TNF-α blockade. In view of this, she commenced intravenous tocilizumab (8 mg/kg every 2 weeks), a humanised monoclonal antibody targeting the IL-6 receptor (IL-6R) that binds to membrane and soluble IL-6R, inhibiting IL-6-mediated signaling. She reported immediate cessation of fever and marked improvement in her energy levels following the first infusion; after the fifth dose, she was in complete clinical and serological remission, now sustained for 24 months. This is one of the first reported cases of a child with MKD treated successfully with tocilizumab and adds to the very limited experience of this treatment for MKD. IL-6 blockade could therefore be an important addition to the armamentarium for the treatment of this rare monogenic autoinflammatory disease

Higher health literacy is associated with better glycemic control in adults with type 1 diabetes:a cohort study among 1399 Danes

Aim: Self-management of diabetes is influenced by a range of factors including the ability to access, understand, appraise, and use of health information in everyday life, which can collectively be called health literacy. We investigated associations between nine domains of health literacy and HbA1c level in people with type 1 diabetes.Methods: A cross-sectional study was conducted with 1399 people with type 1 diabetes attending a Danish specialist diabetes clinic. Health literacy was assessed using the nine-domain Health Literacy Questionnaire. The association between health literacy and HbA1c was analyzed using linear regression with adjustment for age, sex, educational attainment and diabetes duration. Results: Of the 1399 participants, 50% were women, mean age was 54 years, and mean HbA1c was 61 mmol/mol (7.8%). Higher health literacy scores were associated with lower HbA1c levels across eight of nine health literacy domains. This association remained significant after adjusting for educational attainment. Among the domains, \u27Actively managing my health\u27 had the strongest impact on HbA1c. This was in turn predicted by \u27Appraising health information\u27, \u27Having sufficient information to manage health\u27, and \u27Social support for health\u27. Conclusions: Higher health literacy levels are associated with lower HbA1c regardless of educational background. This study highlights the importance of healthcare provision to respond to the health literacy levels of people with diabetes and to the possible need to provide program designed to enhance health literacy

Superpulsed low-level laser therapy protects skeletal muscle of mdx mice against damage, inflammation and morphological changes delaying dystrophy progression.

Aim: To evaluate the effects of preventive treatment with low-level laser therapy (LLLT) on progression of dystrophy in mdx mice. Methods: Ten animals were randomly divided into 2 experimental groups treated with superpulsed LLLT (904 nm, 15 mW, 700 Hz, 1 J) or placebo-LLLT at one point overlying the tibialis anterior muscle (bilaterally) 5 times per week for 14 weeks (from 6th to 20th week of age). Morphological changes, creatine kinase (CK) activity and mRNA gene expression were assessed in animals at 20th week of age. Results: Animals treated with LLLT showed very few morphological changes in skeletal muscle, with less atrophy and fibrosis than animals treated with placebo-LLLT. CK was significantly lower (p = 0.0203) in animals treated with LLLT (864.70 U.l−1, SEM 226.10) than placebo (1708.00 U.l−1, SEM 184.60). mRNA gene expression of inflammatory markers was significantly decreased by treatment with LLLT (p<0.05): TNF-α (placebo-control = 0.51 µg/µl [SEM 0.12], - LLLT = 0.048 µg/µl [SEM 0.01]), IL-1β (placebo-control = 2.292 µg/µl [SEM 0.74], - LLLT = 0.12 µg/µl [SEM 0.03]), IL-6 (placebo-control = 3.946 µg/µl [SEM 0.98], - LLLT = 0.854 µg/µl [SEM 0.33]), IL-10 (placebo-control = 1.116 µg/µl [SEM 0.22], - LLLT = 0.352 µg/µl [SEM 0.15]), and COX-2 (placebo-control = 4.984 µg/µl [SEM 1.18], LLLT = 1.470 µg/µl [SEM 0.73]). Conclusion: Irradiation of superpulsed LLLT on successive days five times per week for 14 weeks decreased morphological changes, skeletal muscle damage and inflammation in mdx mice. This indicates that LLLT has potential to decrease progression of Duchenne muscular dystrophy

Real-time whole-genome sequencing for routine typing, surveillance, and outbreak detection of verotoxigenic Escherichia coli.

Fast and accurate identification and typing of pathogens are essential for effective surveillance and outbreak detection. The current routine procedure is based on a variety of techniques, making the procedure laborious, time-consuming, and expensive. With whole-genome sequencing (WGS) becoming cheaper, it has huge potential in both diagnostics and routine surveillance. The aim of this study was to perform a real-time evaluation of WGS for routine typing and surveillance of verocytotoxin-producing Escherichia coli (VTEC). In Denmark, the Statens Serum Institut (SSI) routinely receives all suspected VTEC isolates. During a 7-week period in the fall of 2012, all incoming isolates were concurrently subjected to WGS using IonTorrent PGM. Real-time bioinformatics analysis was performed using web-tools (www.genomicepidemiology.org) for species determination, multilocus sequence type (MLST) typing, and determination of phylogenetic relationship, and a specific VirulenceFinder for detection of E. coli virulence genes was developed as part of this study. In total, 46 suspected VTEC isolates were characterized in parallel during the study. VirulenceFinder proved successful in detecting virulence genes included in routine typing, explicitly verocytotoxin 1 (vtx1), verocytotoxin 2 (vtx2), and intimin (eae), and also detected additional virulence genes. VirulenceFinder is also a robust method for assigning verocytotoxin (vtx) subtypes. A real-time clustering of isolates in agreement with the epidemiology was established from WGS, enabling discrimination between sporadic and outbreak isolates. Overall, WGS typing produced results faster and at a lower cost than the current routine. Therefore, WGS typing is a superior alternative to conventional typing strategies. This approach may also be applied to typing and surveillance of other pathogens

Mechanical and Electronic Properties of MoS2_2 Nanoribbons and Their Defects

We present our study on atomic, electronic, magnetic and phonon properties of one dimensional honeycomb structure of molybdenum disulfide (MoS$_2$) using first-principles plane wave method. Calculated phonon frequencies of bare armchair nanoribbon reveal the fourth acoustic branch and indicate the stability. Force constant and in-plane stiffness calculated in the harmonic elastic deformation range signify that the MoS$_2$ nanoribbons are stiff quasi one dimensional structures, but not as strong as graphene and BN nanoribbons. Bare MoS$_2$ armchair nanoribbons are nonmagnetic, direct band gap semiconductors. Bare zigzag MoS$_2$ nanoribbons become half-metallic as a result of the (2x1) reconstruction of edge atoms and are semiconductor for minority spins, but metallic for the majority spins. Their magnetic moments and spin-polarizations at the Fermi level are reduced as a result of the passivation of edge atoms by hydrogen. The functionalization of MoS$_2$ nanoribbons by adatom adsorption and vacancy defect creation are also studied. The nonmagnetic armchair nanoribbons attain net magnetic moment depending on where the foreign atoms are adsorbed and what kind of vacancy defect is created. The magnetization of zigzag nanoribbons due to the edge states is suppressed in the presence of vacancy defects.Comment: 11 pages, 5 figures, first submitted at November 23th, 200

Whole genome sequencing,molecular typing and in vivovirulence of OXA-48-producingEscherichia coli isolates includingST131 H30-Rx, H22 and H41subclones

Carbapenem-resistant Enterobacteriaceae, including the increasingly reported OXA-48 Escherichia coli producers, are an emerging public health threat worldwide. Due to their alarming detection in our healthcare setting and their possible presence in the community, seven OXA-48-producing, extraintestinal pathogenic E. coli were analysed by whole genome sequencing as well as conventional tools, and tested for in vivo virulence. As a result, five E. coli OXA-48-producing subclones were detected (O25:H4-ST131/PST43-fimH30-virotype E; O25:H4-ST131/PST9-fimH22-virotype D5, O16:H5-ST131/ PST506-fimH41; O25:H5-ST83/PST207 and O9:H25-ST58/PST24). Four ST131 and one ST83 isolates satisfied the ExPEC status, and all except the O16:H5 ST131 isolate were UPEC. All isolates exhibited local inflammatory response with extensive subcutaneous necrosis but low lethality when tested in a mouse sepsis model. The blaOXA-48 gene was located in MOBP131/IncL plasmids (four isolates) or within the chromosome (three ST131 H30-Rx isolates), carried by Tn1999-like elements. All, except the ST83 isolate, were multidrug-resistant, with additional plasmids acting as vehicles for the spread of various resistance genes. This is the first study to analyse the whole genome sequences of blaOXA-48-positive ST131, ST58 and ST83 E. coli isolates in conjunction with experimental data, and to evaluate the in vivo virulence of blaOXA-48 isolates, which pose an important challenge to patient management

Red (660 nm) and infrared (830 nm) low-level laser therapy in skeletal muscle fatigue in humans: what is better?

In animal and clinical trials low-level laser therapy (LLLT) using red, infrared and mixed wavelengths has been shown to delay the development of skeletal muscle fatigue. However, the parameters employed in these studies do not allow a conclusion as to which wavelength range is better in delaying the development of skeletal muscle fatigue. With this perspective in mind, we compared the effects of red and infrared LLLT on skeletal muscle fatigue. A randomized double-blind placebo-controlled crossover trial was performed in ten healthy male volunteers. They were treated with active red LLLT, active infrared LLLT (660 or 830 nm, 50 mW, 17.85 W/cm2, 100 s irradiation per point, 5 J, 1,785 J/cm2 at each point irradiated, total 20 J irradiated per muscle) or an identical placebo LLLT at four points of the biceps brachii muscle for 3 min before exercise (voluntary isometric elbow flexion for 60 s). The mean peak force was significantly greater (p < 0.05) following red (12.14%) and infrared LLLT (14.49%) than following placebo LLLT, and the mean average force was also significantly greater (p < 0.05) following red (13.09%) and infrared LLLT (13.24%) than following placebo LLLT. There were no significant differences in mean average force or mean peak force between red and infrared LLLT. We conclude that both red than infrared LLLT are effective in delaying the development skeletal muscle fatigue and in enhancement of skeletal muscle performance. Further studies are needed to identify the specific mechanisms through which each wavelength acts