Perioperative use of dexmedetomidine is associated with reduction in postoperative analgesic requirements. This study examined whether dexmedetomidine added to i.v. patient-controlled analgesia (PCA) ...morphine could improve analgesia while reducing opioid-related side-effects.
In this double-blinded, randomized, controlled study, 100 women undergoing abdominal total hysterectomy were allocated to receive either morphine 1 mg ml−1 alone (Group M) or morphine 1 mg ml−1 plus dexmedetomidine 5 μg ml−1 (Group D) for postoperative i.v. PCA, which was programmed to deliver 1 ml per demand with a 5 min lockout interval and no background infusion. Cumulative PCA requirements, pain intensities, cardiovascular and respiratory variables, and PCA-related adverse events were recorded for 24 h after operation.
Compared with Group M, patients in Group D required 29% less morphine during the 0–24 h postoperative period and reported significantly lower pain levels from the second postoperative hour onwards and throughout the study. Whereas levels of sedation were similar between the groups at each observational time point, decreases in heart rate and mean blood pressure from presurgery baseline at 1, 2, and 4 h after operation were significantly greater in Group D (by a range of 5–7 beats min−1 and 10–13%, respectively). The 4–24 h incidence of nausea was significantly lower in Group D (34% vs 56.3%, P<0.05). There was no bradycardia, hypotension, oversedation, or respiratory depression.
The addition of dexmedetomidine to i.v. PCA morphine resulted in superior analgesia, significant morphine sparing, less morphine-induced nausea, and was devoid of additional sedation and untoward haemodynamic changes.
Human infections with zoonotic coronaviruses (CoVs), including severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV, have raised great public health concern ...globally. Here, we report a novel bat-origin CoV causing severe and fatal pneumonia in humans.
We collected clinical data and bronchoalveolar lavage (BAL) specimens from five patients with severe pneumonia from Wuhan Jinyintan Hospital, Hubei province, China. Nucleic acids of the BAL were extracted and subjected to next-generation sequencing. Virus isolation was carried out, and maximum-likelihood phylogenetic trees were constructed.
Five patients hospitalized from December 18 to December 29, 2019 presented with fever, cough, and dyspnea accompanied by complications of acute respiratory distress syndrome. Chest radiography revealed diffuse opacities and consolidation. One of these patients died. Sequence results revealed the presence of a previously unknown β-CoV strain in all five patients, with 99.8% to 99.9% nucleotide identities among the isolates. These isolates showed 79.0% nucleotide identity with the sequence of SARS-CoV (GenBank NC_004718) and 51.8% identity with the sequence of MERS-CoV (GenBank NC_019843). The virus is phylogenetically closest to a bat SARS-like CoV (SL-ZC45, GenBank MG772933) with 87.6% to 87.7% nucleotide identity, but is in a separate clade. Moreover, these viruses have a single intact open reading frame gene 8, as a further indicator of bat-origin CoVs. However, the amino acid sequence of the tentative receptor-binding domain resembles that of SARS-CoV, indicating that these viruses might use the same receptor.
A novel bat-borne CoV was identified that is associated with severe and fatal respiratory disease in humans.
Liver disorders have been recognized as one major health concern. Fucoidan, a sulfated polysaccharide extracted from the brown seaweed Fucus serratus, has previously been reported as an ...anti-inflammatory and antioxidant. However, the discovery and validation of its hepatoprotective properties and elucidation of its mechanisms of action are still unknown. The objective of the current study was to investigate the effect and possible modes of action of a treatment of fucoidan against thioacetamide (TAA)-induced liver injury in male C57BL/6 mice by serum biochemical and histological analyses. The mouse model for liver damage was developed by the administration of TAA thrice a week for six weeks. The mice with TAA-induced liver injury were orally administered fucoidan once a day for 42 days. The treated mice showed significantly higher body weights; food intakes; hepatic antioxidative enzymes (catalase, glutathione peroxidase (GPx), and superoxide dismutase (SOD)); and a lower serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and C-reactive protein (CRP) levels. Additionally, a reduced hepatic IL-6 level and a decreased expression of inflammatory-related genes, such as cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) mRNA was observed. These results demonstrated that fucoidan had a hepatoprotective effect on liver injury through the suppression of the inflammatory responses and acting as an antioxidant. In addition, here, we validated the use of fucoidan against liver disorders with supporting molecular data.
Stimuli-responsive ion nanochannels have attracted considerable attention in various fields because of their remote controllability of ionic transportation. For photoresponsive ion nanochannels, ...however, achieving precise regulation of ion conductivity is still challenging, primarily due to the difficulty of programmable structural changes in confined environments. Moreover, the relationship between noncontact photo-stimulation in nanoscale and light-induced ion conductivity has not been well understood. In this work, a versatile design for fabricating guard cell-inspired photoswitchable ion channels is presented by infiltrating azobenzene-cross-linked polymer (AAZO-PDAC) into nanoporous anodic aluminum oxide (AAO) membranes. The azobenzene-cross-linked polymer is formed by azobenzene chromophore (AAZO)-cross-linked poly(diallyldimethylammonium chloride) (PDAC) with electrostatic interactions. Under UV irradiation, the trans-AAZO isomerizes to the cis-AAZO, causing the volume compression of the polymer network, whereas, in darkness, the cis-AAZO reverts to the trans-AAZO, leading to the recovery of the structure. Consequently, the resultant nanopore sizes can be manipulated by the photomechanical effect of the AAZO-PDAC polymers. By adding ionic liquids, the ion conductivity of the light-driven ion nanochannels can be controlled with good repeatability and fast responses (within seconds) in multiple cycles. The ion channels have promising potential in the applications of biomimetic materials, sensors, and biomedical sciences.
Huntington's disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The expanded CAG repeats are translated into polyglutamine (polyQ), ...causing aberrant functions as well as aggregate formation of mutant Htt. Effective treatments for HD are yet to be developed.
Here, we report a novel dual-function compound, N(6)-(4-hydroxybenzyl)adenine riboside (designated T1-11) which activates the A(2A)R and a major adenosine transporter (ENT1). T1-11 was originally isolated from a Chinese medicinal herb. Molecular modeling analyses showed that T1-11 binds to the adenosine pockets of the A(2A)R and ENT1. Introduction of T1-11 into the striatum significantly enhanced the level of striatal adenosine as determined by a microdialysis technique, demonstrating that T1-11 inhibited adenosine uptake in vivo. A single intraperitoneal injection of T1-11 in wildtype mice, but not in A(2A)R knockout mice, increased cAMP level in the brain. Thus, T1-11 enters the brain and elevates cAMP via activation of the A(2A)R in vivo. Most importantly, addition of T1-11 (0.05 mg/ml) to the drinking water of a transgenic mouse model of HD (R6/2) ameliorated the progressive deterioration in motor coordination, reduced the formation of striatal Htt aggregates, elevated proteasome activity, and increased the level of an important neurotrophic factor (brain derived neurotrophic factor) in the brain. These results demonstrate the therapeutic potential of T1-11 for treating HD.
The dual functions of T1-11 enable T1-11 to effectively activate the adenosinergic system and subsequently delay the progression of HD. This is a novel therapeutic strategy for HD. Similar dual-function drugs aimed at a particular neurotransmitter system as proposed herein may be applicable to other neurotransmitter systems (e.g., the dopamine receptor/dopamine transporter and the serotonin receptor/serotonin transporter) and may facilitate the development of new drugs for other neurodegenerative diseases.
Abstract
Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we ...show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of
Txndc5
markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFβ1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFβ1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of
Txndc5
mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF.
Background
Atrial fibrillation (AF) prevalence increases with age. Aging affects the substrate properties of the left atrium (LA) and the outcomes of catheter ablation for treating AF. We ...investigated the AF trigger distribution and catheter ablation outcomes in patients of different ages with AF.
Methods
1585 patients with AF (1181 paroxysmal and 404 non‐ paroxysmal AF) who had undergone catheter ablation were enrolled. The patients were divided into young (20–40 year‐old, n = 175), middle‐aged (41–64 year‐old, n = 1134), and old (≥ 65 year‐old, n = 276) groups. Electrophysiological characteristics and AF trigger sites were recorded.
Result
The incidence of AF with only non‐pulmonary vein (non‐PV) foci was higher in the young group than in the other groups (8.6% vs. 3.6% vs. 3.3%, p < 0.01). Non‐PV foci were more commonly located in the superior vena cava (SVC) in the young group than in the other groups (13.1% vs. 7.8% vs. 6.5%, p = 0.03). The left atrium (LA) mean voltage was higher and the incidence of very late recurrence after AF ablation was lower in the young group than in the other groups. However, the final AF recurrence rate after multiple procedures and complication rates were similar among all the groups at a mean follow‐up of 5.6 years.
Conclusion
The young patients with AF had a higher incidence of only non‐PV foci, mostly located in SVC, than the middle‐aged and old patients. Our study highlights the importance of identifying the non‐PV foci in catheter ablation of young patients with AF.
The metabolically healthy obese (MHO) characterized by the absence of metabolic syndrome have shown superior cardiorespiratory fitness (CRF) and similar muscular strength as compared with the ...metabolically unhealthy obese (MUO). However, this finding might be biased by the baseline sedentary behavior in the general population. This study utilized 3669 physically active military males aged 18-50 years in Taiwan. Obesity and metabolically unhealthy were respectively defined as body mass index ≥ 27.5 kg/m
and presence of at least two major components of the metabolic syndrome, according to the International Diabetes Federation criteria for Asian male adults. Four groups were accordingly classified as the metabolically healthy lean (MHL, n = 2510), metabolically unhealthy lean (MUL, n = 331), MHO (n = 181) and MUO (n = 647). CRF was evaluated by time for a 3-km run, and muscular strengths were separately assessed by numbers of push-up and sit-up within 2 min. Analysis of covariance was utilized to compare the difference in each exercise performance between groups adjusting for age, service specialty, smoking, alcohol intake and physical activity. The metabolic syndrome prevalence in MUL and MUO was 49.8% and 47.6%, respectively. The performance of CRF did not differ between MHO and MUO (892.3 ± 5.4 s and 892.6 ± 3.0 s, p = 0.97) which were both inferior to MUL and MHL (875.2 ± 4.0 s and 848.6 ± 1.3 s, all p values < 0.05). The performance of muscular strengths evaluated by 2-min push-ups did not differ between MUL and MUO (45.3 ± 0.6 and 45.2 ± 0.4, p = 0.78) which were both less than MHO and MHL (48.4 ± 0.8 and 50.6 ± 0.2, all p values < 0.05). However, the performance of 2-min sit-ups were only superior in MHL (48.1 ± 0.1) as compared with MUL, MHO and MUO (45.9 ± 0.4, 46.7 ± 0.5 and 46.1 ± 0.3, respectively, all p values < 0.05). Our findings suggested that in a physically active male cohort, the MHO might have greater muscle strengths, but have similar CRF level compared with the MUO.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus emerged in late 2019 leading to the COVID-19 disease pandemic that triggered socioeconomic turmoil worldwide. A precise, prompt, ...and affordable diagnostic assay is essential for the detection of SARS-CoV-2 as well as its variants. Antibody against SARS-CoV-2 spike (S) protein was reported as a suitable strategy for therapy and diagnosis of COVID-19. We, therefore, developed a quick and precise phase-sensitive surface plasmon resonance (PS-SPR) biosensor integrated with a novel generated anti-S monoclonal antibody (S-mAb). Our results indicated that the newly generated S-mAb could detect the original SARS-CoV-2 strain along with its variants. In addition, a SARS-CoV-2 pseudovirus, which could be processed in BSL-2 facility was generated for evaluation of sensitivity and specificity of the assays including PS-SPR, homemade target-captured ELISA, spike rapid antigen test (SRAT), and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Experimentally, PS-SPR exerted high sensitivity to detect SARS-CoV-2 pseudovirus at 589 copies/ml, with 7-fold and 70-fold increase in sensitivity when compared with the two conventional immunoassays, including homemade target-captured ELISA (4 × 10
copies/ml) and SRAT (4 × 10
copies/ml), using the identical antibody. Moreover, the PS-SPR was applied in the measurement of mimic clinical samples containing the SARS-CoV-2 pseudovirus mixed with nasal mucosa. The detection limit of PS-SPR is calculated to be 1725 copies/ml, which has higher accuracy than homemade target-captured ELISA (4 × 10
copies/ml) and SRAT (4 × 10
copies/ml) and is comparable with qRT-PCR (1250 copies/ml). Finally, the ability of PS-SPR to detect SARS-CoV-2 in real clinical specimens was further demonstrated, and the assay time was less than 10 min. Taken together, our results indicate that this novel S-mAb integrated into PS-SPR biosensor demonstrates high sensitivity and is time-saving in SARS-CoV-2 virus detection. This study suggests that incorporation of a high specific recognizer in SPR biosensor is an alternative strategy that could be applied in developing other emerging or re-emerging pathogenic detection platforms.
Esophageal squamous cell carcinoma (ESCC) is prevalent in some geographical regions of the world. ESCC development presents a multistep pathogenic process from inflammation to invasive cancer; ...however, what is critical in these processes and how they evolve is largely unknown, obstructing early diagnosis and effective treatment. Here, we create a mouse model mimicking human ESCC development and construct a single-cell ESCC developmental atlas. We identify a set of key transitional signatures associated with oncogenic evolution of epithelial cells and depict the landmark dynamic tumorigenic trajectories. An early downregulation of CD8
response against the initial tissue damage accompanied by the transition of immune response from type 1 to type 3 results in accumulation and activation of macrophages and neutrophils, which may create a chronic inflammatory environment that promotes carcinogen-transformed epithelial cell survival and proliferation. These findings shed light on how ESCC is initiated and developed.
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