Wireless Direct Microampere Current in Wound Healing: Clinical and Immunohistological Data from Two Single Case Reports

Chronic pressure ulcers are hard-to-heal wounds that decrease the patient’s quality of life. Wireless Micro Current Stimulation (WMCS) is an innovative, non-invasive, similar to electrode-based electrostimulation (ES) technology, that generates and transfers ions that are negatively-charged to the injured tissue, using accessible air gases as a transfer medium. WMCS is capable of generating similar tissue potentials, as electrode-based ES, for injured tissue. Here, through immunohistochemistry, we intended to characterize the induced tissue healing biological mechanisms that occur during WMCS therapy. Two single cases of bedridden due to serious stroke white men with chronic non-healing pressure ulcers have been treated with WMCS technology. WMCS suppresses inflammatory responses by decreasing the aggregation of granulocytes, followed by stimulating myofibroblastic activity and a new formation of collagen fibers, as depicted by immunohistochemistry. As a result, WMCS provides a special adjunct or stand-alone therapy choice for chronic and non-healing injuries, similar to electrode-based ES, but with added (i.e., contactless) benefits towards its establishment as a routine clinical wound healing regime

VAV1 and BAFF, via NFκB pathway, are genetic risk factors for myasthenia gravis

Objective To identify novel genetic loci that predispose to early‐onset myasthenia gravis (EOMG) applying a two‐stage association study, exploration, and replication strategy. Methods Thirty‐four loci and one confirmation loci, human leukocyte antigen (HLA)‐DRA, were selected as candidate genes by team members of groups involved in different research aspects of MG. In the exploration step, these candidate genes were genotyped in 384 EOMG and 384 matched controls and significant difference in allele frequency were found in eight genes. In the replication step, eight candidate genes and one confirmation loci were genotyped in 1177 EOMG patients and 814 controls, from nine European centres. Results Allele frequency differences were found in four novel loci: CD86, AKAP12, VAV1, B‐cell activating factor (BAFF), and tumor necrosis factor‐alpha (TNF‐α), and these differences were consistent in all nine cohorts. Haplotype trend test supported the differences in allele frequencies between cases and controls. In addition, allele frequency difference in female versus male patients at HLA‐DRA and TNF‐α loci were observed. Interpretation The genetic associations to EOMG outside the HLA complex are novel and of interest as VAV1 is a key signal transducer essential for T‐ and B‐cell activation, and BAFF is a cytokine that plays important roles in the proliferation and differentiation of B‐cells. Moreover, we noted striking epistasis between the predisposing VAV1 and BAFF haplotypes; they conferred a greater risk in combination than alone. These, and CD86, share the same signaling pathway, namely nuclear factor‐kappaB (NFκB), thus implicating dysregulation of proinflammatory signaling in predisposition to EOMG

Novel genetic risk variants for pediatric celiac disease

Background: Celiac disease is a complex chronic immune-mediated disorder of the small intestine. Today, the pathobiology of the disease is unclear, perplexing differential diagnosis, patient stratification, and decision-making in the clinic. Methods: Herein, we adopted a next-generation sequencing approach in a celiac disease trio of Greek descent to identify all genomic variants with the potential of celiac disease predisposition. Results: Analysis revealed six genomic variants of prime interest: SLC9A4 c.1919G gt A, KIAA1109 c.2933T gt C and c. 4268_4269delCCinsTA, HoxB6 c.668C gt A, HoxD12 c.418G gt A, and NCK2 c.745_746delAAinsG, from which NCK2 c.745_746delAAinsG is novel. Data validation in pediatric celiac disease patients of Greek (n=109) and Serbian (n=73) descent and their healthy counterparts (n=111 and n=32, respectively) indicated that HoxD12 c.418G gt A is more prevalent in celiac disease patients in the Serbian population (P lt 0.01), while NCK2 c.745_746delAAinsG is less prevalent in celiac disease patients rather than healthy individuals of Greek descent (P = 0. 03). SLC9A4 c.1919G gt A and KIAA1109 c.2933T gt C and c.4268_4269delCCinsTA were more abundant in patients; nevertheless, they failed to show statistical significance. Conclusions: The next-generation sequencing-based family genomics approach described herein may serve as a paradigm towards the identification of novel functional variants with the aim of understanding complex disease pathobiology

Microcurrent Stimulation Triggers MAPK Signaling and TGF-β1 Release in Fibroblast and Osteoblast-Like Cell Lines

Wound healing constitutes an essential process for all organisms and involves a sequence of three phases. The disruption or elongation of any of these phases can lead to a chronic or non-healing wound. Electrical stimulation accelerates wound healing by mimicking the current that is generated in the skin after any injury. Here, we sought to identify the molecular mechanisms involved in the healing process following in vitro microcurrent stimulation—a type of electrotherapy. Our results concluded that microcurrents promote cell proliferation and migration in an ERK 1/2- or p38-dependent way. Furthermore, microcurrents induce the secretion of transforming growth factor-beta-1 (TGF-β1) in fibroblasts and osteoblast-like cells. Interestingly, transcriptomic analysis uncovered that microcurrents enhance the transcriptional activation of genes implicated in Hedgehog, TGF-β1 and MAPK signaling pathways. Overall, our results demonstrate that microcurrents may enhance wound closure through a combination of signal transductions, via MAPK’s phosphorylation, and the transcriptional activation of specific genes involved in the healing process. These mechanisms should be further examined in vivo, in order to verify the beneficial effects of microcurrents in wound or fracture healing

Prediction of Long-Term Survival after Coronary Artery Bypass with Bilateral Internal Thoracic Artery Grafting: External Validation of A Contemporary Nomogram

Background: This study aimed to verify the external validation of a contemporary nomogram in predicting long-term survival after an isolated coronary artery bypass with bilateral internal thoracic artery grafting (CABG-BITA). Methods: Consecutive patients who underwent CABG-BITA at a single center were included in the study. All the predictors of the original risk score (age, diabetes mellitus, chronic obstructive pulmonary disease, congestive heart failure, chronic renal failure, old myocardial infarction, ejection fraction, intra-aortic balloon pump and peripheral arterial disease) were available for analysis. Results: Among the 2846 consecutive patients, a total of 1176 (41.3%) deaths were recorded during the 31,383 patient years of follow-up. The median EuroSCORE II was 2.35, and the median follow-up was 11.1 years. The risk score showed 72.7% overall discriminatory ability as measured by Harrell’s concordance statistic. It showed satisfactory calibration at 10, 15 and 20 years of follow-up. The risk score showed a time-varying nonlinear effect, and accordingly, adjusted long-term survival predictions were calculated. There were subgroups (scores < 50 points) with favorable 20-year survival rates ranging from 77% to 60%. Higher risk subgroups (scores > 90 points) showed poor 20-year survival rates ranging from 22% to 4%. Conclusions: The validated risk score represents a useful algorithm for the detection of patients who could benefit after CABG-BITA with respect to long-term survival. Although further multi-center studies are required worldwide to reveal the usefulness of this score in the clinical setting, its wide adoption may act as a motivation for cardiac surgeons resulting in higher numbers of CABG-BITA procedures

Real-Time Assessment of E-Cigarettes and Conventional Cigarettes Emissions: Aerosol Size Distributions, Mass and Number Concentrations

Cigarette smoke is a complex mixture of chemical compounds which are emitted during the processes of tobacco combustion. Electronic cigarettes (e-cigs) are expected to produce less harmful compounds due to the absence of tobacco leaf combustion. However, potential risks of the passive exposure to the aerosol exhaled by e-cig users have been raised in the last decade. In this study, the aerosols with diameter less than 1 μm (PM1) produced by vaping of various e-cig liquids were compared to those generated by smoking conventional cigarettes in real time. The mass and number concentration along with the number size distribution were measured in a closed room of 35 m3 volume. Our results showed that aerosols emitted from e-cig liquids had a different profile compared to those from conventional cigarettes. Although e-cigs initially produced higher particle mass and number concentrations, their emissions had much shorter lifetime of approximately 10–20 s, in comparison with the conventional and hand-rolling cigarette particulate emissions which had a dissipation time of approximately 1.4 h in a 35 m3 room. E-cigs emitted aerosols which volatilized rapidly, as they probably consisted almost only of propylene glycol and/or vegetable glycerin

mRNA levels of Fgf21 and relevant genes in mouse primary hepatocytes after simvastatin treatment.

<p>mRNA levels of Fgf21 (<b>A</b>), Pcsk9 (<b>B</b>), Acox1 (<b>C</b>), Cyp4a10 (<b>D</b>) in primary hepatocytes treated with vehicle or simvastatin (3 different doses) for 12 hours. Data are presented as the means ±SEM from 3 individual experiments, each of which included 3 technical replicates. *P<0.05 (compared with vehicle treatment).</p

Primer sequences used for qRT-PCR.

<p>Primer sequences used for qRT-PCR.</p

Expression of Fgf21 in liver and serum after simvastatin treatment in mice.

<p><b>A.</b> Immunoblotting analysis of Fgf21 in the livers of 3-month old male mice treated with simvastatin (0.1% w/w in chow) for 1 week. Immunoblots for Ampkα and elf2a and Coomassie blue staining of the gel were used as loading controls. <b>B.</b> Relative Fgf21 protein levels as assessed by immunoblotting after normalization to elf2a levels. Data are presented as the mean ± SEM. n = 5 per treatment. *P<0.05. <b>C, D, E, F, G, H</b>. mRNA levels of Fgf21(C), Hmgcr (D), Pcsk9 (E), Acox1 (F), Cyp4a10 (G), Cyp7a1 (H) in the livers of 3-month old male mice treated with simvastatin (0.1% w/w in chow) for 1 week. Relative mRNA levels were assessed by qRT-PCR. Data are presented as the mean ±SEM. n = 7–8 per treatment. *P<0.05. <b>I.</b> Assessment of serum Fgf21 levels by ELISA in 3-month old male mice treated with vehicle or simvastatin. Data are presented as the mean ±SEM. n = 7–8 per treatment. *P<0.05.</p

Fgf21 mRNA levels after intraperitoneal administration of simvastatin.

<p>Fgf21 (<b>A</b>) and Pcsk9 (<b>B</b>) mRNA levels in the liver of mice administered vehicle (control) or simvastatin intraperitoneally twice (20 and 12 hours before sacrifice). Data are presented as the mean ± SEM, n = 10 per treatment. *P<0.05 compared with control.</p