A Novel Circulating MicroRNA for the Detection of Acute Myocarditis.

BACKGROUND: The diagnosis of acute myocarditis typically requires either endomyocardial biopsy (which is invasive) or cardiovascular magnetic resonance imaging (which is not universally available). Additional approaches to diagnosis are desirable. We sought to identify a novel microRNA for the diagnosis of acute myocarditis. METHODS: To identify a microRNA specific for myocarditis, we performed microRNA microarray analyses and quantitative polymerase-chain-reaction (qPCR) assays in sorted CD4+ T cells and type 17 helper T (Th17) cells after inducing experimental autoimmune myocarditis or myocardial infarction in mice. We also performed qPCR in samples from coxsackievirus-induced myocarditis in mice. We then identified the human homologue for this microRNA and compared its expression in plasma obtained from patients with acute myocarditis with the expression in various controls. RESULTS: We confirmed that Th17 cells, which are characterized by the production of interleukin-17, are a characteristic feature of myocardial injury in the acute phase of myocarditis. The microRNA mmu-miR-721 was synthesized by Th17 cells and was present in the plasma of mice with acute autoimmune or viral myocarditis but not in those with acute myocardial infarction. The human homologue, designated hsa-miR-Chr8:96, was identified in four independent cohorts of patients with myocarditis. The area under the receiver-operating-characteristic curve for this novel microRNA for distinguishing patients with acute myocarditis from those with myocardial infarction was 0.927 (95% confidence interval, 0.879 to 0.975). The microRNA retained its diagnostic value in models after adjustment for age, sex, ejection fraction, and serum troponin level. CONCLUSIONS: After identifying a novel microRNA in mice and humans with myocarditis, we found that the human homologue (hsa-miR-Chr8:96) could be used to distinguish patients with myocarditis from those with myocardial infarction. (Funded by the Spanish Ministry of Science and Innovation and others.).

Skene's Gland Cyst - Case Report of a 2-Year-Old Girl.

BACKGROUND: Skene's glands are the two largest paraurethral glands and the female homologue to the prostate glands. When their ducts become obstructed, cysts may be formed. This usually occurs in adult women. Most cases reported in pediatrics are neonatal, with a single report in a prepubertal girl. CASE REPORT: We present a 25-month-old girl with a 7 mm nontender, solid, oval, pink-orange paraurethral mass, with no change over a five-month period. Histopathology revealed the cyst to be lined with transitional epithelium consistent with a Skene's gland cyst. The child did well with no sequalae. CONCLUSION: We describe a Skene's gland cyst found in a prepubertal child.

Synthesis and biological evaluation of 4-hydroxy-methylpiperidinyl-N-benzyl-acylarylhydrazone hybrids designed as novel multifunctional drug candidates for Alzheimer's disease.

The search for new drug candidates against Alzheimer's disease (AD) remains a complex challenge for medicinal chemists due to its multifactorial pathogenesis and incompletely understood physiopathology. In this context, we have explored the molecular hybridization of pharmacophore structural fragments from known bioactive molecules, aiming to obtain a novel molecular architecture in new chemical entities capable of concomitantly interacting with multiple targets in a so-called multi-target directed ligands (MTDLs) approach. This work describes the synthesis of 4-hydroxymethyl)piperidine-N-benzyl-acyl-hydrazone derivatives 5a-l, designed as novel MTDLs, showing improved multifunctional properties compared to the previously reported parent series of N-benzyl-(3-hydroxy)piperidine-acyl-hydrazone derivatives 4. The new improved derivatives were studied in silico, regarding their mode of interaction with AChE enzyme, and in vitro, for evaluation of their effects on the selective inhibition of cholinesterases, cellular antioxidant, and neuroprotective activities as their cytotoxicity in human neuroblastoma (SH-SY5Y) cells. Overall, compound PQM-181 (5 k) showed the best balanced selective and non-competitive inhibition of AChE (IC50 = 5.9 µM, SI > 5.1), with an additional antioxidant activity (IC50 = 7.45 µM) against neuronal t-BOOH-induced oxidative stress and neuroprotective ability against neurotoxicity elicited by both t-BOOH and OAß1-42, and a moderate ability to interfere in Aß1-42 aggregates, with low cytotoxicity and good predictive druggability properties, suggesting a multifunctional pharmacological profile suitable for further drug development against AD.

LRP1B Expression as a Putative Predictor of Response to Pegylated Liposomal Doxorubicin Treatment in Ovarian Cancer.

BACKGROUND: Pegylated liposomal doxorubicin (PLD) is among the most active therapies for recurrent/progressive ovarian cancer (OC). Low-density lipoprotein receptor-related protein 1B (LRP1B) is one of the 10 most significantly deleted genes in human cancers. It mediates endocytosis of several factors from the cellular environment including liposomes. Although the LRP1B role in cancer has not been fully disclosed, its contribution to resistance to liposomal therapies has been hypothesized. This study aimed to evaluate the impact of LRP1B protein as a possible marker of response to PLD in patients with OC. METHODS: LRP1B expression and response to PLD were analyzed in OC cell lines by qRT-PCR and PrestoBlue viability assay, respectively. LRP1B protein expression was evaluated for the first time, in tumor samples from PLD-treated patients and controls (other chemotherapies) by immunohistochemistry. Association of LRP1B staining score (determined based on intensity and percentage of positively stained cells) with clinicopathological features, response to therapy and survival outcomes was evaluated. RESULTS: OC cells with increased expression of LRP1B were more sensitive to PLD. LRP1B staining score was associated with clinicopathological features, response to therapy, and survival outcomes. Higher LRP1B levels were associated with prolonged progression-free survival. This association was more evident in patients treated with PLD and in responders to PLD. CONCLUSION: Our results support a possible role of LRP1B as a predictor of response to PLD in patients with OC.

Chronic infarct size after spontaneous coronary artery dissection: implications for pathophysiology and clinical management.

AIMS: To report the extent and distribution of myocardial injury and its impact on left ventricular systolic function with cardiac magnetic resonance imaging (CMR) following spontaneous coronary artery dissection (SCAD) and to investigate predictors of myocardial injury. METHODS AND RESULTS: One hundred and fifty-eight angiographically confirmed SCAD-survivors (98% female) were phenotyped by CMR and compared in a case-control study with 59 (97% female) healthy controls (44.5 ± 8.4 vs. 45.0 ± 9.1 years). Spontaneous coronary artery dissection presentation was with non-ST-elevation myocardial infarction in 95 (60.3%), ST-elevation myocardial infarction (STEMI) in 52 (32.7%), and cardiac arrest in 11 (6.9%). Left ventricular function in SCAD-survivors was generally well preserved with small reductions in ejection fraction (57 ± 7.2% vs. 60 ± 4.9%, P < 0.01) and increases in left ventricular dimensions (end-diastolic volume: 85 ± 14 mL/m2 vs. 80 ± 11 mL/m2, P < 0.05; end-systolic volume: 37 ± 11 mL/m2 vs. 32 ± 7 mL/m2, P <0.01) compared to healthy controls. Infarcts were small with few large infarcts (median 4.06%; range 0-30.9%) and 39% having no detectable late gadolinium enhancement (LGE). Female SCAD patients presenting with STEMI had similar sized infarcts to female Type-1 STEMI patients age <75 years. Multivariate modelling demonstrated STEMI at presentation, initial TIMI 0/1 flow, multivessel SCAD, and a Beighton score >4 were associated with larger infarcts [>10% left ventricular (LV) mass]. CONCLUSION: The majority of patients presenting with SCAD have no or small infarctions and preserved ejection fraction. Patients presenting with STEMI, TIMI 0/1 flow, multivessel SCAD and those with features of connective tissue disorders are more likely to have larger infarcts.

Chiral Spin Spirals at the Surface of the van der Waals Ferromagnet Fe3GeTe2.

Topologically protected magnetic structures provide a robust platform for low power consumption devices for computation and data storage. Examples of these structures are skyrmions, chiral domain walls, and spin spirals. Here, we use scanning electron microscopy with polarization analysis to unveil the presence of chiral counterclockwise Néel spin spirals at the surface of a bulk van der Waals ferromagnet Fe3GeTe2 (FGT) at zero magnetic field. These Néel spin spirals survive up to FGT's Curie temperature of TC = 220 K, with little change in the periodicity p = 300 nm of the spin spiral throughout the studied temperature range. The formation of a spin spiral showing counterclockwise rotation strongly suggests the presence of a positive Dzyaloshinskii-Moriya interaction in FGT, which provides the first steps towards the understanding of the magnetic structure of FGT. Our results additionally pave the way for chiral magnetism in van der Waals materials and their heterostructures.

Correlated Exciton Fluctuations in a Two-Dimensional Semiconductor on a Metal.

Excitons in nanoscale materials can exhibit fluorescence fluctuations. Intermittency is pervasive in zero-dimensional emitters such as single molecules and quantum dots. In contrast, two-dimensional semiconductors are generally regarded as stable light sources. Noise contains, however, valuable information about a material. Here, we demonstrate fluorescence fluctuations in a monolayer semiconductor due to sensitivity to its nanoscopic environment focusing on the case of a metal film. The fluctuations are spatially correlated over tens of micrometers and follow power-law statistics, with simultaneous changes in emission intensity and lifetime. At low temperatures, an additional spectral contribution from interface trap states emerges with fluctuations that are correlated with neutral excitons and anticorrelated with trions. Mastering exciton fluctuations has implications for light-emitting devices such as single-photon sources and could lead to novel excitonic sensors. The quantification of fluorescence fluctuations, including imaging, unlocks a set of promising tools to characterize and exploit two-dimensional semiconductors and their interfaces.

Functional and metabolic imaging in transthoracic biopsies guided by computed tomography.

OBJECTIVES: CT-guided biopsy of indeterminate lung lesions sometimes provides insufficient histological results due to tumor necrosis. Functional and metabolic methods such as DWI-MR and PET-CT may help by directing sample collection to a lesion area of greater biological representativeness. The objective is to evaluate the histopathological results based on findings on ADC and SUV levels in lung lesions suspected for primary cancer. METHODS: Tissue samples were evaluated after undergoing biopsies guided by either DWI-MR or PET-CT findings. In each patient, sample collection from two lesion areas was guided by local ADC and SUV. Values were used to define areas of low vs. high suspicion for cancer. RESULTS: Patients who underwent DWI-MR had median lesion size of 78.0 mm. Areas of higher suspicion (HSA) had a median ADC of 1.1 × 10-3 mm2/s, while areas of lower suspicion (LSA) had median ADC of 1.8 × 10-3 mm2/s (p = 0.0001). All HSA samples and 71.43% of LSA samples were positive for cancer (p = 0.0184). Patients who performed PET-CT had median lesion size of 61.0 mm. Median SUV was 7.1 for HSA and 3.9 for LSA (p = 0.0002). Positivity for cancer was observed in 76.9% of samples for both HSA and LSA (p = 0.0522). CONCLUSION: Use of DWI-MR and PET-CT showed that tumors are functional and metabolically heterogeneous and that this heterogeneity has implications for histopathological diagnosis. KEY POINTS: • Lung cancer is heterogeneous regarding functional and metabolic imaging. • Tumor heterogeneity may have implications in histopathological diagnosis. • Intralesional lower levels of ADC target highly suspected areas with a significant improvement in lung cancer diagnosis.

Improving cognitive and physical function through 12-weeks of resistance training in older adults: Randomized controlled trial.

We performed a randomized, controlled trial to analyse the effects of resistance training (RT) on cognitive and physical function among older adults. Fifty participants (mean age 67 years, ~60% woman) were randomly assigned to an RT program or a control group. Participants allocated to RT performed three sets of 10-15RM in nine exercises, three times per week, for 12-weeks. Control group did not perform any exercise. Variables included cognitive (global and executive function) and physical function (gait, mobility and strength) outcomes. At completion of the intervention, RT was shown to have significantly mitigated the drop in selective attention and conflict resolution performance (Stroop test: -494.6; 95%CI: -883.1; -106.1) and promoted a significant improvement in working memory (digit span forward: -0.6; 95%CI: -1.0; -0.1 and forward minus backward: -0.9; 95% CI: -1.6; -0.2) and verbal fluency (animal naming: +1.4, 95%CI 0.3, 2.5). No significant between-group differences were observed for other cognitive outcomes. Regarding physical function, at completion of the intervention, the RT group demonstrated improved fast-pace gait performance (-0.3; 95% CI: -0.6; -0.0) and 1-RM (+21.4 kg; 95%CI: 16.6; 26.2). No significant between-group differences were observed for other mobility-related outcomes. In conclusion, RT improves cognitive and physical function of older adults.

Design, Synthesis and Biological Evaluation of Novel Triazole N-acylhydrazone Hybrids for Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that involves different pathogenic mechanisms. In this regard, the goal of this study was the design and synthesis of new compounds with multifunctional pharmacological activity by molecular hybridization of structural fragments of curcumin and resveratrol connected by an N-acyl-hydrazone function linked to a 1,4-disubstituted triazole system. Among these hybrid compounds, derivative 3e showed the ability to inhibit acetylcholinesterase activity, the intracellular formation of reactive oxygen species as well as the neurotoxicity elicited by Aß42 oligomers in neuronal SH-SY5Y cells. In parallel, compound 3e showed a good profile of safety and ADME parameters. Taken together, these results suggest that 3e could be considered a lead compound for the further development of AD therapeutics.

Early restenosis of resorbable magnesium scaffolds: Optical coherence tomography findings.

Resorbable Magnesium Scaffolds (RMS) represent an interesting alternative to current drug-eluting stents. Current data from clinical trials seems to confirm good performance of these new devices with low rates of late device failure. Little is known about mechanisms leading to RMS failure. Herein, we present the first description of an early RMS in-scaffold restenosis. Optical coherence tomography (OCT) analysis at implantation detected acute non-severe malapposition and underexpansion as main promoters of RMS failure. OCT during in-scaffold restenosis intervention confirmed early severe neointimal proliferation and RMS late recoil and dismantling as the main mechanisms of device failure. We hypothesize that the fast resorption process of RMS may lead to an early loss of radial strength, that could favor late recoil, acquired underexpansion, device dismantling and might interact with distribution of sirolimus. This case also illustrates that OCT is pivotal to unravel both acute and acquired mechanisms related to RMS failure.

Spin-Orbit Torques in NbSe2/Permalloy Bilayers.

We present measurements of current-induced spin-orbit torques generated by NbSe2, a fully metallic transition-metal dichalcogenide material, made using the spin-torque ferromagnetic resonance (ST-FMR) technique with NbSe2/Permalloy bilayers. In addition to the out-of-plane Oersted torque expected from current flow in the metallic NbSe2 layer, we also observe an in-plane antidamping torque with torque conductivity σS ≈ 103 (ℏ/2e)(Ωm)-1 and indications of a weak field-like contribution to the out-of-plane torque oriented opposite to the Oersted torque. Furthermore, in some samples we also measure an in-plane field-like torque with the form m̂ × z, where m̂ is the Permalloy magnetization direction and z is perpendicular to the sample plane. The size of this component varies strongly between samples and is not correlated with the NbSe2 thickness. A torque of this form is not allowed by the bulk symmetries of NbSe2 but is consistent with symmetry breaking by a uniaxial strain that might result during device fabrication.

Diagnostic accuracy of a hybrid approach of instantaneous wave-free ratio and fractional flow reserve using high-dose intracoronary adenosine to characterize intermediate coronary lesions: Results of the PALS (Practical Assessment of Lesion Severity) prospective study.

OBJECTIVES: We sought to investigate the diagnostic accuracy of instantaneous wave-free ratio (iFR) and high-dose intracoronary adenosine fractional flow reserve (IC-FFR) compared with classical intravenous adenosine fractional flow reserve (IV-FFR) to assess coronary stenosis severity. The usefulness of two hybrid strategies combining iFR and high-dose IC-FFR was also evaluated. BACKGROUND: Physiological assessment of intermediate coronary stenoses to guide revascularization is currently recommended. METHODS: Consecutive real-world patients with angiographically intermediate coronary stenosis (40-80% diameter stenosis) were prospectively included in the PALS (Practical Assessment of Lesion Severity) study. In every target lesion iFR, high-dose IC-FFR and IV-FFR were systematically measured to assess the accuracy of an hybrid sequential approach combining iFR and IC-FFR. RESULTS: A total of 106 patients with 121 intermediate coronary lesions were analyzed. Both, iFR and IC-FFR showed a significant correlation with IV-FFR (iFR: r = 0.60, 95%CI 0.48-0.70; IC-FFR: r = 0.88; 95%CI: 0.83-0.92). High-dose IC-FFR provided lower FFR values than IV-FFR (0.81 ± 0.08 vs. 0.82 ± 0.09, P = 0.25). Using a receiver-operating-characteristic curve an optimal iFR threshold of 0.91 for the screening test was identified. A sequential test strategy (initial iFR followed by IC-FFR only in lesions with iFR <0.91) yielded an excellent diagnostic accuracy (96.7%, 95%CI 96.7-99.1%) with a sensitivity, specificity, positive and negative predicted values of 100%, 94.7%, 91.8%, and 100%, respectively. A hybrid approach using the previously described iFR gray zone (0.85-0.94) also provided an excellent diagnostic accuracy (95%, 95%CI: 89.5-98.1%). CONCLUSIONS: In patients with intermediate coronary lesions a hybrid strategy by using a sequential approach of iFR and high-dose IC-FFR, provided a very good diagnostic performance to identify physiologically significant stenoses. © 2017 Wiley Periodicals, Inc.

Distant Metastases in Uterine Leiomyosarcomas: The Wide Variety of Body Sites and Time Intervals to Metastatic Relapse.

Uterine leiomyosarcoma (U-LMS) is the most frequent malignant gynecologic mesenchymal tumor, often develops distant metastases and has a dismal prognosis. In this study we aim to characterize the body sites and time to metastasis in women with U-LMS. We evaluated 130 U-LMSs with distant metastases including a series of patients diagnosed at 2 tertiary centers, as well as cases published in the literature, found using a PubMed query. Data collected included clinic-pathologic features, time to first metastasis, and survival. Survival analysis was performed using univariable and multivariable Cox regression model. The most frequent metastatic sites were: lung (67.7%), cranial/intracranial (16.2%), skin/soft tissues (15.3%), and bone (13.8%). Other sites included thyroid, salivary gland, heart, liver, pancreas, adrenal gland, bowel, and breast. Metastases were histologically identical to primary tumors. Median time to first metastasis was highly variable (median: 24 mo; range, 1 mo to 26 y). Lung and peritoneum were the earlier metastatic sites; 21.4% of patients with U-LMS limited to the pelvis develop metastasis >5 yr after diagnosis. Lung metastases significantly associated with other distant metastases. Regarding treatment, only resection of metastases significantly influenced postmetastasis survival in multivariable analysis (hazard ratio: 0.49, P=0.015). In conclusion, U-LMS display highly variable sites of distant metastases. Metastases in unusual locations are sometimes the first to be detected, and not uncommonly, single and prone to surgical resection. There is also a wide range of time intervals to first metastasis, highlighting the need of long-term follow-up, high level of suspicion, and appropriate diagnostic confirmation.

Safety and efficacy of HepaSphere 50-100 µm in the treatment of hepatocellular carcinoma.

AIM: To evaluate the effects of HepaSphere 50-100 µm (Merit Medical) as a doxorubicin carrier and embolization agent for the treatment of hepatocellular carcinoma (HCC). MATERIAL AND METHODS: A prospective analysis of 18 patients recruited from a national cancer center was conducted. This analysis evaluated the efficacy and safety of HepaSphere, as expressed by the treatment response rate (measured by the modified Response Evaluation Criteria in Solid Tumors, mRECIST) and by the prevalence of treatment-related adverse events, respectively. RESULTS: The cohort was predominantly male, with a mean age of 69 years. The objective response rate (complete + partial response) was 53.3%. The variable most likely to be associated with objective response was Barcelona Clinic Liver Cancer (BCLC) staging. The most prevalent adverse events were nausea, vomiting and abdominal pain. CONCLUSION: HepaSphere chemoembolization yielded a substantial objective response rate with an acceptable toxicity profile and should be considered an option for HCC treatment.

Mediastinal lymph nodes and pulmonary nodules in children: MDCT findings in a cohort of healthy subjects.

OBJECTIVE: Existing data are very limited on incidentally detected pulmonary nodules or mediastinal lymph nodes in healthy children who undergo chest MDCT. We aimed to evaluate the prevalence, distribution, and average dimensions of these occasional findings in a cohort of otherwise healthy patients. MATERIALS AND METHODS: Two radiologists reviewed in consensus the scans of patients referred for chest MDCT during the preoperative workup for pectus carinatum or pectus excavatum treatments. Exclusion criteria included the presence of any documented malignancy (by date of MDCT or during the 2 years after the examination), history of recent infections, or trauma. Patients' records were assessed after 2 years for the development of any malignancy. RESULTS: A total of 99 individuals (63 boys, 36 girls; mean age, 13.5 years; range, 4-18 years) who fulfilled the study criteria were evaluated. The presence of at least one pulmonary nodule was observed in 75% of the patients, with a mean diameter of 2.8 mm. Of a total number of 225 pulmonary nodules, only 24 (10.7%) were calcified. Mediastinal lymph nodes were also identified in 81% of the cases, with a maximum diameter of 7 mm (smallest axis). CONCLUSION: The presence of pulmonary nodules or mediastinal lymph nodes on the basis of preoperative chest MDCT scans in healthy children is frequent. Given that 95% of the nodules and 100% of the lymph nodes measured less than 6 mm and 7 mm, respectively, we conclude that incidental findings under these limits are very unlikely to be pathologic.

Using phase to recognize English phonemes and their distinctive features in the brain.

The neural mechanisms used by the human brain to identify phonemes remain unclear. We recorded the EEG signals evoked by repeated presentation of 12 American English phonemes. A support vector machine model correctly recognized a high percentage of the EEG brain wave recordings represented by their phases, which were expressed in discrete Fourier transform coefficients. We show that phases of the oscillations restricted to the frequency range of 2-9 Hz can be used to successfully recognize brain processing of these phonemes. The recognition rates can be further improved using the scalp tangential electric field and the surface Laplacian around the auditory cortical area, which were derived from the original potential signal. The best rate for the eight initial consonants was 66.7%. Moreover, we found a distinctive phase pattern in the brain for each of these consonants. We then used these phase patterns to recognize the consonants, with a correct rate of 48.7%. In addition, in the analysis of the confusion matrices, we found significant similarity-differences were invariant between brain and perceptual representations of phonemes. These latter results supported the importance of phonological distinctive features in the neural representation of phonemes.