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To evaluate the association of intracranial non-stenotic atherosclerotic plaque with cerebral small vessel disease (CSVD) imaging markers in a CSVD population using 3.0 T high-resolution magnetic resonance imaging (HRMRI), which was validated in embolic stroke of undetermined source (ESUS) cohort. We retrospectively recruited consecutive patients who were diagnosed with CSVD or ESUS from January 2015 to December 2019. All patients underwent intracranial HRMRI to assess intracranial non-stenotic atherosclerotic plaques. Baseline and imaging data were collected and were measured among all patients. Among 153 patients with CSVD, there were 59 with intracranial atherosclerotic plaque (IAP) and 94 with non-IAP, including 36 with intracranial atherosclerotic complicated plaque (IACP). Among 227 ESUS patients, there were 155 with IAP and 72 with non-IAP, including 127 with IACP. In the CSVD population, we found that: (1) CSVD burden was associated with IAP (p = 0.036) and IACP (p = 0.008); (2) IAP was associated with white matter hyperintensity (51% vs. 34%; P = 0.039), and IACP was associated with lacunes (69% vs. 35%; P = 0.009) and enlarge perivascular space (69% vs. 39%; P = 0.022). A similar association of CSVD imaging markers with IAP or IACP was found in the ESUS population. Furthermore, the association of unilateral IAP or IACP with CSVD imaging markers of ipsilateral hemisphere was identified in the two cohorts. This is the first report that intracranial non-stenotic atherosclerotic plaque, especially complicated plaque, is closely associated with CSVD imaging markers, which provide further evidence for the association of large artery atherosclerosis with CSVD. [ABSTRACT FROM AUTHOR]

3′-Sialyllactose (3′-SL), a natural prebiotic, maintains immune homeostasis and exerts anti-inflammatory and anti-arthritic effects. Although regulatory T cells (Tregs) prevent excessive inflammation and maintain immune tolerance, the effect of 3′-SL on Treg regulation is unclear. This study aimed to investigate the effect of 3′-SL on Treg responses in atopic dermatitis (AD) pathogenesis. Oral administration of 3′-SL reduced AD-like symptoms such as ear, epidermal, and dermal thickness in repeated topical application of house dust mites (HDM) and 2,4-dinitrochlorobenzene (DNCB). 3′-SL inhibited IgE, IL-1β, IL-6, and TNF-α secretion and markedly downregulated AD-related cytokines including IL-4, IL-5, IL-6, IL-13, IL-17, IFN-γ, TNF-α, and Tslp through regulation of NF-κB in ear tissue. Additionally, in vitro assessment of Treg differentiation revealed that 3′-SL directly induced TGF-β-mediated Treg differentiation. Furthermore, 3′-SL administration also ameliorated sensitization and elicitation of AD pathogenesis by suppressing mast cell infiltration and production of IgE and pro-inflammatory cytokines in mouse serum by mediating the Treg response. Furthermore, Bifidobacterium population was also increased by 3′-SL administration as prebiotics. Our data collectively show that 3′-SL has therapeutic effects against AD progression by inducing Treg differentiation, downregulating AD-related cytokines, and increasing the Bifidobacterium population. [ABSTRACT FROM AUTHOR]

To identify differential metabolites and metabolic pathways and provide guidance for the novel biomarkers for diagnosis and prognosis of amyotrophic lateral sclerosis (ALS). ALS patients and people without nervous diseases were recruited. Metabolomic analysis was performed using gas chromatography-mass spectrometry (GC/MS). The orthogonal projections to latent structures discriminant analysis (OPLS-DA) were used to identify differential metabolites. Kyoto Encyclopedia of Genes and Genomes and MetaboAnalyst were used to identify metabolic pathways. 75 metabolites were detected and aligned. The OPLS-DA showed the metabolomic profile of ALS patients and those in the fast-progression and slow-progression ALS groups differed from that of CTRL (p < 0.05). The levels of maltose, glyceric acid, lactic acid, beta-alanine, phosphoric acid, glutamic acid, ethanolamine and glycine in ALS were significantly higher, while 2,4,6-tri-tert-butylbenzenethiol was lower. Glycine, serine and threonine metabolism, D-glutamine and D-glutamate metabolism, alanine, aspartate, and glutamate metabolism, beta-alanine metabolism, and pyruvate metabolism were significantly altered metabolic pathways in ALS. ROC was used to discriminate ALS from CTRL with an AUC of 0.898 (p < 0.001) using 2,4,6-tri-tert-butylbenzenethiol, beta-alanine, glycine, and ethanolamine. The serum metabolites and metabolic pathways in ALS patients are significantly altered compared with CTRL. These findings may contribute to the early diagnosis of ALS. [ABSTRACT FROM AUTHOR]

A new double-layer, pH-sensitive, composite hydrogel sustained-release system based on polysaccharides and synthetic polymers with combined functions of different inner/outer hydrogels was prepared. The polysaccharides inner core based on sodium alginate (SA) and carboxymethyl cellulose (CMC), was formed by physical crosslinking with pH-sensitive property. The synthetic polymer out-layer with enhanced stability was introduced by chemical crosslinking to eliminate the expansion of inner core and the diffusion of inner content. The physicochemical structure of the double-layer hydrogels was characterized. The drug-release results demonstrated that the sustained-release effect of the hydrogels for different model drugs could be regulated by changing the composition or thickness of the hydrogel layer. The significant sustained-release effect for BSA and indomethacin indicated that the bilayer hydrogel can be developed into a novel sustained delivery system for bioactive substance or drugs with potential applications in drugs and functional foods. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure. A large proportion of genetic cause remains unexplained, especially in idiopathic DCM. We performed target next-generation sequencing of 102 genes which were known causes or candidate genes for cardiomyopathies and channelpathies in 118 prospectively recruited Han Chinese patients with idiopathic DCM. 41 of the 118 patients carried 40 pathogenic or likely pathogenic variants, providing a molecular diagnosis in 34.7% of patients. 32 of these variants were novel. TTN truncating variants were predominant, with a frequency of 31.0%, followed by variants of LMNA (14.3%), RBM20 (4.8%), and NEXN (4.8%). These 4 genes accounted for over half variants identified. No significant difference in clinical characteristics or rates of reaching the composite end point (cardiac transplantation and death from cardiac causes) between pathogenic or likely pathogenic variant carriers and noncarriers (hazard ratio 1.11, 95% CI: 0.41 to 3.00), or between patients with TTN truncating variants or without (hazard ratio 0.49, 95% CI: 0.36 to 6.10). In our prospective study, we first determined the overall genetic profiles and genotype-phenotype correlations in Han Chinese idiopathic DCM patients, which could provide insight for genetic diagnosis of DCM in this population. [ABSTRACT FROM AUTHOR]

The aim of this study was to localize the anatomic distribution of upper motor neuron (UMN) loss through examining cortical thickness at the clinical onset of amyotrophic lateral sclerosis (ALS) and explore motor manifestation in functionally impaired body region attribute to impairment of lower motor neuron (LMN) or UMN or mixed LMN and UMN? The clinical features, cortical thickness of corresponding areas from different body regions in MRI and electromyography (EMG) data were collected from 108 classical ALS patients. The cortical thickness was thinner in ALS group than control group in bilateral head-face and upper-limb areas (p < 0.05). In head-face area, the cortical thickness of bulbar-onset group was significantly lower than that of control groups (p < 0.05). In upper-limb areas, the cortical thickness of cervical-onset group was significantly thinner than that of control group. Notably, the bulbar ALSFRS-R subscore was correlated with cortical thickness in bilateral head-face areas (p < 0.05). The bulbar ALSFRS-R subscore of the positive LMN damage group was lower compared to that of the negative LMN damage group (P < 0.001). The limb ALSFRS-R subscore correlated with compound muscle action potential (CMAP) amplitudes of median, ulnar, peroneal, and tibial nerves (P < 0.001), but was not related to cortical thickness. In conclusion, the UMN degeneration in ALS was derived from focal initiation, bulbar- and cervical-onset may date from head-face and upper-limb areas in motor homunculus cortex, respectively. The bulbar dysfunction was resulted from the mixed UMN and LMN impairment, while limb dysfunction derived mostly from LMN loss. [ABSTRACT FROM AUTHOR]

To explore differential diagnosis value of dissociated lower-limb muscle impairment, we performed a retrospective analysis of clinical and electrophysiological features in 141 lower-limb involved ALS patients, 218 normal controls, 67 disease controls, and 32 lumbar spondylosis disease patients. The dissociated lower-limb muscle impairment was quantified by plantar flexion and dorsiflexion strength, compound muscle action potentials ratio of peroneal and tibial nerves (split index, SI) and semi-quantitative scoring scale of denervation potential. Clinical features: the proportion of decreased dorsiflexion was higher than decreased planter flexor strength in lower-limb involved ALS (77.2%vs 38.3%). Electrophysiological features: (1) SI in ALS was the lowest among four groups (Test statistic = 40.57, p < 0.001). (2) Percentage of positive denervation potential was higher in tibialis anterior than gastrocnemius muscle (χ2 = 87.12, p < 0.001). ROC curve: the SI cutoff was 0.52 and 0.33 respectively to differentiate ALS from lumbar spondylosis disease and peripheral neuropathy. Lower-limb involved ALS patients exhibited "split leg" phenomenon. The SI value could be used as an electrophysiological marker to differentiate ALS from lumbar spondylosis disease and peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Graft acceptance without the need for immunosuppressive drugs is the ultimate goal of transplantation therapy. In murine liver transplantation, allografts are accepted across major histocompatibility antigen complex barriers without the use of immunosuppressive drugs and constitute a suitable model for research on immunological rejection and tolerance. MicroRNA (miRNA) has been known to be involved in the immunological responses. In order to identify mRNAs in spontaneous liver allograft tolerance, miRNA expression in hepatic allografts was examined using this transplantation model. According to the graft pathological score and function, miR-146a, 15b, 223, 23a, 27a, 34a and 451 were upregulated compared with the expression observed in the syngeneic grafts. In contrast, miR-101a, 101b and 148a were downregulated. Our results demonstrated the alteration of miRNAs in the allografts and may indicate the role of miRNAs in the induction of tolerance after transplantation. Furthermore, our data suggest that monitoring the graft expression of novel miRNAs may allow clinicians to differentiate between rejection and tolerance. A better understanding of the tolerance inducing mechanism observed in murine hepatic allografts may provide a therapeutic strategy for attenuating allograft rejection. [ABSTRACT FROM AUTHOR]

Hydrogen exerts beneficial effects in disease animal models of ischemia-reperfusion injury as well as inflammatory and neurological disease. Additionally, molecular hydrogen is useful for various novel medical and therapeutic applications in the clinical setting. In the present study, the hydrogen concentration in rat blood and tissue was estimated. Wistar rats were orally administered hydrogen super-rich water (HSRW), intraperitoneal and intravenous administration of hydrogen super-rich saline (HSRS), and inhalation of hydrogen gas. A new method for determining the hydrogen concentration was then applied using high-quality sensor gas chromatography, after which the specimen was prepared via tissue homogenization in airtight tubes. This method allowed for the sensitive and stable determination of the hydrogen concentration. The hydrogen concentration reached a peak at 5 minutes after oral and intraperitoneal administration, compared to 1 minute after intravenous administration. Following inhalation of hydrogen gas, the hydrogen concentration was found to be significantly increased at 30 minutes and maintained the same level thereafter. These results demonstrate that accurately determining the hydrogen concentration in rat blood and organ tissue is very useful and important for the application of various novel medical and therapeutic therapies using molecular hydrogen. [ABSTRACT FROM AUTHOR]

We analyzed the clinicopathological features of 9 breast malignant fibrous histiocytoma (MFH) patients. Immunohistochemistry was used to make both diagnosis and differential diagnosis, and to identify prognostic factors. All tumors lacked epithelial markers but expressed mesenchymal markers, suggesting a mesenchymal origin. Of the five cases expressing Ki-67, two of three patients with axillary lymph node involvement died between 6-8 months, and two died at 17 and 26 months after diagnosis. The two remaining cases, with low Ki-67 expression, had no recurrent or metastatic disease at 145 months after diagnosis. Previous studies have shown that surgery is the primary treatment of choice, but no clear benefit from adjuvant chemotherapy was observed. We demonstrate that axillary lymph node involvement and high expression of Ki-67 are associated with poorer prognosis. A literature review indicates surgery remains the first choice for MFH, but benefits from adjuvant chemotherapy remain unclear. [ABSTRACT FROM AUTHOR]

Pluronic L61 unimers, which are biomacromolecular modulators, and curcumin, a small-molecule modulator, were co-formulated into pH-sensitive micelles to reveal the full synergistic potential of combination drug treatments to reverse multidrug resistance (MDR). Compared to monotherapy, combined therapy significantly improved the cytotoxicity, cellular uptake and apoptotic effects of doxorubicin (DOX) against MCF-7/ADR cells. In mechanistic studies, both L61 and curcumin enhanced the cytotoxic effect by acting on mitochondrial signalling pathways. The compounds selectively accumulated in the mitochondria and disabled the mitochondria by dissipating the mitochondrial membrane potential, decreasing the ATP levels, and releasing cytochrome c, which initiated a cascade of caspase-9 and caspase-3 reactions. Furthermore, both curcumin and L61 down-regulated the expression and function of P-gp in response to drug efflux from the MCF-7/ADR cells. In the MCF-7/ADR tumour-bearing mouse model, intravenous administration of the combined therapy directly targeted the tumour, as revealed by the accumulation of DiR in the tumour site, which led to a significant inhibition of tumour growth without measurable side effects. In conclusion, co-formulation consisting of L61 and curcumin in pH-sensitive micelles induced significant synergistic effects on the reversal of MDR. Therefore, the intracellular co-delivery of various MDR modulators has great potential to reverse MDR in tumours. [ABSTRACT FROM AUTHOR]