Increased risk of intestinal dysfunction has been reported in patients after
infection (CDI). Enteric glial cells (EGCs), a component of the enteric nervous system (ENS), contribute to gut ...homeostasis. Previous studies showed that adenosine receptors, A2A and A2B, modulate inflammation during CDI. However, it is unknown how these receptors can modulate the EGC response to the
toxins (TcdA and TcdB). We investigated the effects of these toxins on the expression of adenosine receptors in EGCs and the role of these receptors on toxin-induced EGC death. Rat EGCs line were incubated with TcdA or TcdB alone or in combination with adenosine analogues 1h prior to toxins challenge. After incubation, EGCs were collected to evaluate gene expression (adenosine receptors and proinflammatory markers) and cell death.
, WT, A2A, and A2B KO mice were infected with
, euthanized on day 3 post-infection, and cecum tissue was processed. TcdA and TcdB increased A2A and A3 transcripts, as well as decreased A2B. A2A agonist, but not A2A antagonist, decreased apoptosis induced by TcdA and TcdB in EGCs. A2B blocker, but not A2B agonist, diminished apoptosis in EGCs challenged with both toxins. A3 agonist, but not A3 blocker, reduced apoptosis in EGCs challenged with TcdA and TcdB. Inhibition of protein kinase A (PKA) and CREB, both involved in the main signaling pathway driven by activation of adenosine receptors, decreased EGC apoptosis induced by both toxins. A2A agonist and A2B antagonist decreased S100B upregulation induced by
toxins in EGCs.
, infected A2B KO mice, but not A2A, exhibited a decrease in cell death, including EGCs and enteric neuron loss, compared to infected WT mice, reduced intestinal damage and decreased IL-6 and S100B levels in cecum. Our findings indicate that upregulation of A2A and A3 and downregulation of A2B in EGCs and downregulation of A2B in intestinal tissues elicit a protective response against C.
toxins. Adenosine receptors appear to play a regulatory role in EGCs death and proinflammatory response induced by TcdA and TcdB, and thus may be potential targets of intervention to prevent post-CDI intestinal dysmotility.
Clostridioides difficile infection (CDI) is the fifth leading cause of death from nonmalignant gastrointestinal disease in the United States. The contribution of resistance to C. difficile-active ...antibiotics to the outcomes of CDI is unclear. We evaluated the antimicrobial susceptibility of C. difficile isolates in a U.S. hospital and determined associations of clinical variables and binary toxin positivity with antibiotic resistance. C. difficile spores were cultured from fecal specimens of adult patients with CDI for genotyping and antimicrobial susceptibility assay (for clindamycin CLI, fidaxomicin FDX, metronidazole MTZ, moxifloxacin MXF, tigecycline TGC, and vancomycin VAN). Electronic medical records were reviewed for clinical data extraction. Ninety-seven of 130 (75%) fecal samples grew toxigenic C. difficile in culture. Most of the isolates were
(80.4%), and 18.6% and 1% were
and
, respectively. Susceptibility to VAN, MTZ, FDX, TGC, MXF, and CLI was 96%, 94%, 100%, 100%, 8%, and 79%, respectively. Six isolates, all
positive and belonging to the 027 ribotype, were resistant to VAN and/or MTZ. Higher MICs were found in isolates with a mutation in the VAN-related resistance gene
, but not
. In addition,
isolates exhibited higher MICs of VAN, MTZ, TGC, CLI, and MXF compared to
strains. Patients with greater intestinal inflammation or severe disease were more likely to be infected with
strains. Decreased susceptibility to antibiotics is not directly associated with either severe or recurrent CDI. However, antimicrobial susceptibility of C. difficile is decreased in strains positive for the binary toxin gene.
The involvement of the enteric nervous system, which is a source of S100B, in
(
) infection (CDI) is poorly understood although intestinal motility dysfunctions are known to occur following ...infection. Here, we investigated the role of S100B in CDI and examined the S100B signaling pathways activated in
toxin A (TcdA)- and B (TcdB)-induced enteric glial cell (EGC) inflammatory response. The expression of S100B was measured in colon tissues and fecal samples of patients with and without CDI, as well as in colon tissues from
-infected mice. To investigate the role of S100B signaling in
expression induced by TcdA and TcdB, rat EGCs were used. Increased S100B was found in colonic biopsies from patients with CDI and colon tissues from
infected mice. Patients with CDI-promoted diarrhea exhibited higher levels of fecal S100B compared to non-CDI cases. Inhibition of S100B by pentamidine reduced the synthesis of IL-1β, IL-18, IL-6, GMCSF, TNF-α, IL-17, IL-23, and IL-2 and downregulated a variety of NFκB-related genes, increased the transcription (SOCS2 and Bcl-2) of protective mediators, reduced neutrophil recruitment, and ameliorated intestinal damage and diarrhea severity in mice. In EGCs, TcdA and TcdB upregulated
mediated
expression
activation of RAGE/PI3K/NFκB. Thus, CDI appears to upregulate colonic S100B signaling in EGCs, which in turn augment inflammatory response. Inhibition of S100B activity attenuates the intestinal injury and diarrhea caused by
toxins. Our findings provide new insight into the role of S100B in CDI pathogenesis and opens novel avenues for therapeutic interventions.
Purpose: To compare the lipid layer thickness (LLT) using the LipiView® ocular surface interferometer (TearScience® Inc, Morrisville, NC) between the eye treated with glaucoma medication and ...untreated normal eye in the unilateral glaucoma patients, and evaluate the effect of topical glaucoma medication on the LLT parameters in glaucoma eyes. Methods: The participants in this cross-sectional comparative study were unilateral glaucoma patients treated with topical glaucoma medications for more than 12 months. Three LLT parameters (average, minimum, and maximum) obtained by the LipiView® were compared between the glaucomatous eye and normal eye. The factors associated with LLT parameters in the eyes treated with glaucoma medication were investigated with multiple regression analysis. Results: Thirty patients with unilateral normal tension glaucoma were enrolled in the present study. Lipid layer average, minimum, and maximum were 64.83 ± 16.50, 51.63 ± 16.73, and 82.53 ± 20.62 in glaucomatous eyes, 77.26 ± 17.81, 62.83 ± 20.99, and 86.13 ± 15.42 in normal eyes. Lipid layer average and minimum were significantly thinner than those in normal eyes (P < 0.001, P < 0.001, respectively). Longer duration of glaucoma eye drops and a greater number of glaucoma medications were associated with the lower LLT average (β = −0.456, P < 0.001, β = −8.517, P = 0.003, respectively), and increasing glaucoma medications have a significant correlation with lower LLT minimum in glaucoma eyes (β = −8.814, P = 0.026). Conclusion: The present study highlights that patients with long-term glaucoma medications need to be assessed for LLT parameters objectively evaluate their ocular surface health.
Protein phosphorylation is one of the most prevalent posttranslational modifications found in eukaryotic systems. It serves as a key molecular mechanism that regulates protein function in response to ...environmental stimuli. The Mut9-like kinases (MLKs) are a plant-specific family of Ser/Thr kinases linked to light, circadian, and abiotic stress signaling. Here we use quantitative phosphoproteomics in conjunction with global proteomic analysis to explore the role of the MLKs in daily protein dynamics. Proteins involved in light, circadian, and hormone signaling, as well as several chromatin-modifying enzymes and DNA damage response factors, were found to have altered phosphorylation profiles in the absence of MLK family kinases. In addition to altered phosphorylation levels, mlk mutant seedlings have an increase in glucosinolate metabolism enzymes. Subsequently, we show that a functional consequence of the changes to the proteome and phosphoproteome in mlk mutant plants is elevated glucosinolate accumulation and increased sensitivity to DNA damaging agents. Combined with previous reports, this work supports the involvement of MLKs in a diverse set of stress responses and developmental processes, suggesting that the MLKs serve as key regulators linking environmental inputs to developmental outputs.
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•MUT9-LIKE KINASE mutant quantitative proteome and phosphoproteome measured.•Changes to proteome and phosphoproteome are specific to genotype and environment.•Loss of MLKs alters glucosinolate enzyme abundance and metabolism.•Loss of MLKs increases plant sensitivity to UV radiation and DNA damage agents.
The MUT9-like kinases are a family of plant-specific nuclear-localized kinases with roles in diverse signaling pathways, including light sensing, phytohormone perception, and the circadian clock. The proteome and phosphoproteome of compound mlk mutant seedlings have been determined under light and dark conditions. These experiments identify new roles for these kinases regulating secondary plant metabolism and stress responses, tested through metabolite analysis and assaying seedling sensitivity to DNA damaging agents.
Extrahepatic metastasis (EHM) of hepatocellular carcinoma (HCC) is associated with poor outcomes. However, the clinical features and risk factors of EHM of HCC after radiofrequency ablation (RFA) ...remain unclear.
To elucidate the characteristics and risk factors of EHM after RFA for HCC.
From January 2008 to December 2017, we retrospectively enrolled 661 patients who underwent RFA as first-line treatment for HCC at 2 tertiary hospitals. The inclusion criteria were age ≥ 18 years, a diagnosis of HCC, and treatment-naivety. Abdominal computed tomography (CT) or magnetic resonance imaging (MRI) and alpha-fetoprotein measurements were routinely performed at 1 mo after RFA and followed-up at intervals of 3-6 mo. Univariate analyses were performed using the chi-squared test or Student's
-test, and univariate and multivariate analyses were performed
logistic regression, as appropriate.
EHM was diagnosed in 44 patients (6.7%) during a median follow-up period of 1204 days. The 10-year cumulative rate of HCC recurrence and EHM was 92.7% and 33.7%, respectively. Initial recurrence was most often intrahepatic, and the rate of extrahepatic recurrence at initial recurrence was only 1.2%. The median time to the diagnosis of EHM was 2.68 years, and 68.2% of patients developed EHM within 2 years of the first recurrence, regardless of recurrence-free survival and 75.0% of patients developed EHM within 5 years after first recurrence. EHM was mostly diagnosed
abdominal CT/MRI in 33 (75.0%) and 38 of 44 patients (86.4%) with EHM had either positive abdominal CT scan results or serum AFP level elevation. In multivariate analysis, recurrence-free survival < 2 years, ablation zone/tumor size < 2, and alpha-fetoprotein level > 400 IU/mL were associated with a high EHM risk.
EHM occurs following multiple intrahepatic recurrences after RFA and combined contrast-enhanced abdominal CT and serum AFP were useful for surveillance. Patients especially with high-risk factors require close follow-up for EHM.
Several radiolabeled folic acid conjugates have been developed for targeted imaging and therapy. However, the therapeutic concept with radiolabeled folate conjugates has not yet been applied to ...clinical applications owing to the high renal absorbed dose. The effectiveness of targeted radionuclide therapy (TRT) depends primarily on the absorbed dose rate and on the total absorbed dose delivered to the tumor and to normal tissue. Owing to various limitations associated with organ level dosimetry, voxel-based dosimetry has become essential for the assessment of a more accurate absorbed dose during TRT. In this study, we synthesized iron oxide nanoparticle (IONP)-conjugated radiolabeled folate (
Lu-IONP-Folate) and performed voxel-based dosimetry using SPECT/CT images of normal mice through direct Geant4 application for emission tomography (GATE) Monte Carlo (MC) simulation. We also prepared
Lu-Folate and
Lu-IONPs for the comparison of absorbed doses with that of
Lu-IONP-Folate. In addition, we calculated the mean absorbed dose at the organ-level using the medical internal radiation dose (MIRD) schema. The radioactivities of all three radiotracers were mainly accumulated in the liver and kidneys immediately after injection. For the kidneys, the voxel-based absorbed doses obtained with
Lu-IONP-Folate,
Lu-Folate, and
Lu-IONPs were 1.01 ± 0.17, 2.46 ± 0.50, and 0.52 ± 0.08 Gy/MBq, respectively. The renal absorbed dose decreased significantly (∼half) when
Lu-IONP-Folate was used compared with when the
Lu-Folate only was used. The mean absorbed dose values obtained at organ-level using the MIRD schema were comparable to voxel-based absorbed doses estimated with GATE MC. The voxel-based absorbed dose values obtained in this study of individualized activity show that the renal absorbed dose could be reduced to almost half with
Lu-IONP-Folate. Therefore,
Lu-IONP-Folate could be clinically applicable in the TRT of folate receptor-positive cancers in a personalized manner when using the voxel-based dosimetry method.
The laryngeal mask airway supreme (LMA-S) and i-gel are both popular second-generation supraglottic airway devices that have been widely studied in surgical patients, but their differences in ...clinical performance in the elderly are not clear.
We compared the efficacy and safety of the LMA-S and i-gel in anaesthetised and paralysed elderly patients.
A randomised study.
Single-centre trial, study period January 2014 from to October 2016.
One hundred and six elderly patients who underwent urological or orthopaedic surgery with an expected duration less than 2 h.
Patients were allocated to either the LMA-S (n = 53) or i-gel (n = 53) group. All insertions were performed in a standardised manner according to the manufacturers' instructions.
Our primary endpoint was the rate of successful insertion at the first attempt. The adequacy of positive pressure ventilation and airway sealing, fibreoptic laryngoscopy grades and stability of airway maintenance during anaesthesia were also assessed.
Although the rate of successful insertion at the first attempt was similar between the two groups (94.3 vs. 82.7%, P = 0.072), more patients required device manipulation during insertion with the LMA-S than the i-gel (42.3 vs. 18.9%, P = 0.011). Good fibreoptic laryngoscopy grades were significantly more common with the i-gel than the LMA-S (79.3 vs. 55.8%, P = 0.042), and peak inspiratory pressures were lower in the i-gel group both immediately after insertion and at the end of surgery. Leak pressures were significantly higher in the i-gel group than the LMA-S group, both immediately after insertion and at the end of surgery (25.8 vs. 23.0, P = 0.036; and 28.1 vs. 23.7, P < 0.001, respectively).
Both the LMA-S and i-gel were used successfully and safely in elderly patients. However, the i-gel demonstrated better airway sealing than the LMA-S at insertion and during maintenance of anaesthesia.
NCT02026791 at clinicaltrial.gov.
Using an ambidirectional case-control study, we found that the odds of Clostridioides difficile infection (CDI) were 3.38 (P = .01) times higher for patients with multidrug-resistant organism (MDRO) ...colonization compared to those without. MDRO colonization or infection 1-12 months before CDI testing significantly increased risk of positive CDI diagnosis (odds ratio 4.71, P = .02 and odds ratio = 5.03, P = .05, respectively) independent of antibiotic use, age, and comorbidity status. MDRO colonization and infection are associated with CDI, most significantly if they precede CDI.
Objectives/Hypothesis
Caudal septal deviation interrupts normal nasal breathing, due to the narrowing of the external valve area and nasal valve angle. In this study, we found a different approach ...for correction of caudal septal deviation with no associated deformity of the external nose.
Study Design
Individual case–control study.
Methods
The 39 patients completed questionnaires by interviews postoperatively for assessment of nasal obstruction. In addition, patients assessed the severity of their nasal symptoms (i.e., mouth breathing, mouth dryness, hyposmia, rhinorrhea, epistaxis, snoring, postnasal drip, and headache) preoperatively and postoperatively using a visual analog scale (VAS). Improvement in the treatment of nasal obstruction using a VAS and a questionnaire for subjective satisfaction were evaluated 3 months after septoplasty. To evaluate outcomes objectively, endoscopic photographs of the nasal cavity and acoustic rhinometry before and after surgery were evaluated. For comparison between preoperative and postoperative status, the Wilcoxon signed ranks test was used.
Results
Patients reported a significant decrease in the VAS severity of all nasal symptoms. The minimal cross‐sectional area (MCA1) of the convex side after vascular constriction using acoustic rhinometry showed significant widening. Patients were divided into a turbinoplasty group and a nonturbinoplasty group, and the turbinoplasty group showed a significant increase in both the convex side and concave side in MCA1 and in the convex side in the anterior portion of the inferior turbinate.
Conclusions
Endonasal septoplasty using bony batten grafting for caudal septal deviation resulted in an improvement of nasal obstruction symptoms and acoustic rhinometry components.
Level of Evidence
3b Laryngoscope, 124:1771–1776, 2014
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