Alpha-lipoic acid (LA) has become a common ingredient in multivitamin formulas, anti-aging supplements, and even pet food. It is well-defined as a therapy for preventing diabetic polyneuropathies, ...and scavenges free radicals, chelates metals, and restores intracellular glutathione levels which otherwise decline with age. How do the biochemical properties of LA relate to its biological effects? Herein, we review the molecular mechanisms of LA discovered using cell and animal models, and the effects of LA on human subjects. Though LA has long been touted as an antioxidant, it has also been shown to improve glucose and ascorbate handling, increase eNOS activity, activate Phase II detoxification via the transcription factor Nrf2, and lower expression of MMP-9 and VCAM-1 through repression of NF-kappa B. LA and its reduced form, dihydrolipoic acid, may use their chemical properties as a redox couple to alter protein conformations by forming mixed disulfides. Beneficial effects are achieved with low micromolar levels of LA, suggesting that some of its therapeutic potential extends beyond the strict definition of an antioxidant. Current trials are investigating whether these beneficial properties of LA make it an appropriate treatment not just for diabetes, but also for the prevention of vascular disease, hypertension, and inflammation.
Due to the generally poor prognosis of head and neck squamous cell carcinoma (HNSCC), treatment has been intensified, these last decades, leading to an increase of serious side effects. High‐risk ...human papillomavirus (HR‐HPV) infection has been recently etiologically linked to a subset of oropharyngeal squamous cell carcinoma (OPSCC), which is on the increase. These tumors are different, at the clinical and molecular level, when compared to tumors caused by traditional risk factors. Additionally, their prognosis is much more favorable which has led the medical community to consider new treatment strategies. Indeed, it is possible that less intensive treatment regimens could achieve similar efficacy with less toxicity and improved quality of life. Several clinical trials, investigating different ways to de‐escalate treatment, are currently ongoing. In this article, we review these main approaches, discuss the rationale behind them and the issues raised by treatment de‐escalation in HPV‐positive OPSCC.
To measure the performance of smartphone applications that evaluate photographs of skin lesions and provide the user with feedback about the likelihood of malignancy.
Case-control diagnostic accuracy ...study.
Academic dermatology department. PARTICIPANTS AND MATERIALS: Digital clinical images of pigmented cutaneous lesions (60 melanoma and 128 benign control lesions) with a histologic diagnosis rendered by a board-certified dermatopathologist, obtained before biopsy from patients undergoing lesion removal as a part of routine care.
Sensitivity, specificity, and positive and negative predictive values of 4 smartphone applications designed to aid nonclinician users in determining whether their skin lesion is benign or malignant.
Sensitivity of the 4 tested applications ranged from 6.8% to 98.1%; specificity, 30.4% to 93.7%; positive predictive value, 33.3% to 42.1%; and negative predictive value, 65.4% to 97.0%. The highest sensitivity for melanoma diagnosis was observed for an application that sends the image directly to a board-certified dermatologist for analysis; the lowest, for applications that use automated algorithms to analyze images.
The performance of smartphone applications in assessing melanoma risk is highly variable, and 3 of 4 smartphone applications incorrectly classified 30% or more of melanomas as unconcerning. Reliance on these applications, which are not subject to regulatory oversight, in lieu of medical consultation can delay the diagnosis of melanoma and harm users.
Universal prophylaxis for cytomegalovirus (CMV) prevention is viable but, compared with a preemptive strategy, leads to higher incidence of late‐onset disease (LOD) associated with poor patient and ...graft survival. The purpose of this study was to compare LOD with early onset disease (EOD), with a focus on the highest risk kidney transplant recipients (KTRs): CMV seronegative recipients transplanted from seropositive donors (D+R−). Since CMV control depends on both antiviral treatment and specific immune response, we also compared Vδ2‐negative (Vδ2neg) γδ T cell expansion involved in CMV infection resolution. EOD was defined as occurring <3 mo and LOD as occurring >3 mo after transplantation. Depending on the period, universal prophylaxis or preemptive treatment was used. Overall, 168 D+R− KTRs were included between 2003 and 2011. LOD was associated with a lower peak DNAemia (p = 0.04), fewer recurrences (odds ratio 0.16; 95% confidence interval 0.05–0.55; p = 0.01) and shorter anti‐CMV curative treatment (40 vs. 60 days, p < 0.0001). As a corollary, we found that Vδ2neg γδ T cell expansion was faster in LOD than in EOD (31 vs. 168 days after the beginning of CMV disease, p < 0.0001). In D+R− KTRs, universal prophylaxis is associated with more LOD, which had better infection management and a faster immune response. These results support the use of universal prophylaxis over a preemptive strategy and reappraise outcomes of LOD.
In a comparison of the prognosis of early‐ and late‐onset cytomegalovirus (CMV) disease in donor‐positive, recipient‐negative kidney transplant patients, patients with late‐onset CMV disease occurring at the end of universal prophylaxis had better infection management and a faster immune response than patients with earlyonset CMV disease, often occurring in cases of preemptive strategy, supporting the use of universal prophylaxis in these high‐risk patients.
Context. Multi-purpose InSTRument for Astronomy at Low-resolution (MISTRAL) is the new Faint Object Spectroscopic Camera mounted at the folded Cassegrain focus of the 1.93 m telescope of the ...Haute-Provence Observatory (OHP). Aims. We describe the design and components of the instrument and give some details about its operation. Methods. We emphasize in particular the various observing modes and the performance of the detector. A short description of the working environment is also provided. Various types of objects, including stars, nebulae, comets, novae, and galaxies, have been observed during various test phases to evaluate the performance of the instrument. Results. The instrument covers the range of 4000-8000 Å with the blue setting, or from 6000 to 10 000 Å with the red setting, at an average spectral resolution of 700. Its peak efficiency is about 22% at 6000 Å. In spectroscopy, a limiting magnitude of r ~ 19.5 can be achieved for a point source in one hour with a signal-to-noise ratio of 3 in the continuum (and better when emission lines are present). In imaging mode, limiting magnitudes of 20–21 can be obtained in 10–20 mn (with average seeing conditions of 2.5 arcsec at the OHP). The instrument is very user-friendly and can be put into operations in less than 15 mn (rapid change-over from the other instrument in use) if required by the science (e.g. for gamma-ray bursts). Some first scientific results are described for various types of objects, and in particular, for the follow-up of gamma-ray bursts. Conclusions. While some further improvements are still under way, in particular, to facilitate the switch from blue to red setting and add more grisms or filters, MISTRAL is ready for the follow-up of transients and other variable objects, in the soon-to-come era of the Space-based multi-band astronomical Variable Objects Monitor satellite and of the Rubin telescope, for instance.
Flow-diverter stents are an alternative treatment for challenging and recurrent aneurysms. Thrombosis of the sac is thought to induce perianeurysmal brain inflammation, but such phenomena have never ...been studied in flow-diverter devices. We developed imaging data to explain the clinical exacerbation of symptoms after flow-diversion treatment.
Seventeen patients with unruptured aneurysms were treated by using a flow-diverter device. Clinical symptoms and angiographic and MR imaging features were recorded before and after treatment, during both the acute and chronic phases, to look for inflammatory reaction.
Seven of the 17 patients (41%) showed a delayed clinical aggravation of symptoms posttreatment consisting of a headache (n = 7) with aggravation of pre-existing compressive symptoms (n = 4) and the appearance of compressive symptoms (n = 1). This clinical deterioration was transient; it was observed between 3 and 15 days posttreatment and resolved by day 30. MR imaging revealed signs highly suggestive of perianeurysmal inflammation with vasogenic edema and blood-brain barrier breakdown. The association between MR imaging inflammatory features and clinical aggravation was statistically significant. Large aneurysmal size and its proximity to surrounding brain tissue were predictive of this inflammatory reaction after flow diversion.
The main finding of the series is that MR imaging-defined perianeurysmal inflammation is observed with a high frequency after treatment of unruptured aneurysms with flow diverters and is, in most cases, associated with a transient clinical deterioration.
Abstract
CRISPR-Cas9 is a promising technology for gene therapy. However, the ON-target genotoxicity of CRISPR-Cas9 nuclease due to DNA double-strand breaks has received little attention and is ...probably underestimated. Here we report that genome editing targeting globin genes induces megabase-scale losses of heterozygosity (LOH) from the globin CRISPR-Cas9 cut-site to the telomere (5.2 Mb). In established lines, CRISPR-Cas9 nuclease induces frequent terminal chromosome 11p truncations and rare copy-neutral LOH. In primary hematopoietic progenitor/stem cells, we detect 1.1% of clones (7/648) with acquired megabase LOH induced by CRISPR-Cas9. In-depth analysis by SNP-array reveals the presence of copy-neutral LOH. This leads to 11p15.5 partial uniparental disomy, comprising two Chr11p15.5 imprinting centers (
H19/IGF2:IG-DMR/IC1
and
KCNQ1OT1:TSS-DMR/IC2
) and impacting
H19
and
IGF2
expression. While this genotoxicity is a safety concern for CRISPR clinical trials, it is also an opportunity to model copy-neutral-LOH for genetic diseases and cancers.
In this study we identified mechanisms at the colonic mucosa by which MUC2 mucin regulated the production of β-defensin in a proinflammatory milieu but functionally protected susceptible bacteria ...from its antimicrobial effects. The regulator role of MUC2 on production of β-defensin 2 in combination with the proinflammatory cytokine interleukin-1β (IL-1β) was confirmed using purified human colonic MUC2 mucin and colonic goblet cells short hairpin RNA (shRNA) silenced for MUC2. In vivo, Muc2(-/-) mice showed impaired β-defensin mRNA expression and peptide localization in the colon as compared with Muc2(+/-) and Muc2(+/+) littermates. Importantly, purified MUC2 mucin abrogated the antimicrobial activity of β-defensin 2 against nonpathogenic and enteropathogenic Escherichia coli. Sodium metaperiodate oxidation of MUC2 removed the capacity of MUC2 to stimulate β-defensin production and MUC2's inhibition of defensin antimicrobial activity. This study highlights that a defective MUC2 mucin barrier, typical in inflammatory bowel diseases, may lead to deficient stimulation of β-defensin 2 and an unbalanced microbiota that favor the growth of β-defensin-resistant microbes such as Clostridium difficile.
Articular cartilage has a low capacity for spontaneous repair. To promote the repair of this tissue, the transfer of autologous chondrocytes using a three-dimensional matrix appears promising. In ...this context, the aim of the present work was to investigate the potential use of autologous rabbit nasal chondrocytes (RNC) associated with an injectable self-setting cellulose-based hydrogel (Si-HPMC). Firstly, the influence of Si-HPMC on chondrocytic phenotype was investigated by real-time PCR for specific chondrocyte markers (type II collagen and aggrecan) and type I collagen. Thereafter, autologous RNC were amplified in vitro for 4 weeks before transplantation with Si-HPMC into a rabbit articular cartilage defect followed by analysis 6 weeks later. Implants were histologically characterized for the presence of sulfated GAG and type II collagen. Transcripts analysis indicated that dedifferentiated RNC recovered expression of the main chondrocytic markers after in vitro three-dimensional culture within Si-HPMC. Histological analysis of autologous RNC transplanted in an articular cartilage defect revealed the formation of repair tissue with a histological organization similar to that of healthy articular cartilage. In addition, immunohistological analysis of type II collagen suggested that the repair tissue was a hyaline-like cartilage. Si-HPMC hydrogel associated with nasal chondrocytes therefore appears a promising injectable tissue engineering device for the repair of articular cartilage. Biotechnol. Bioeng. 2009;102: 1259-1267.
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