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1.
Toxicol Sci ; 2024 Jun 19.
Article in English | MEDLINE | ID: mdl-38897660

ABSTRACT

Proarrhythmic cardiotoxicity remains a substantial barrier to drug development as well as a major global health challenge. In vitro human pluripotent stem cell-based new approach methodologies have been increasingly proposed and employed as alternatives to existing in vitro and in vivo models that do not accurately recapitulate human cardiac electrophysiology or cardiotoxicity risk. In this study, we expanded the capacity of our previously established three-dimensional human cardiac microtissue model to perform quantitative risk assessment by combining it with a physiologically based pharmacokinetic model, allowing a direct comparison of potentially harmful concentrations predicted in vitro to in vivo therapeutic levels. This approach enabled the measurement of concentration responses and margins of exposure for two physiologically relevant metrics of proarrhythmic risk (ie, action potential duration and triangulation assessed by optical mapping) across concentrations spanning three orders of magnitude. The combination of both metrics enabled accurate proarrhythmic risk assessment of four compounds with a range of known proarrhythmic risk profiles (ie, quinidine, cisapride, ranolazine, and verapamil) and demonstrated close agreement with their known clinical effects. Action potential triangulation was found to be a more sensitive metric for predicting proarrhythmic risk associated with the primary mechanism of concern for pharmaceutical-induced fatal ventricular arrhythmias, delayed cardiac repolarization due to inhibition of the rapid delayed rectifier potassium channel, or hERG channel. This study advances human induced pluripotent stem cell-based three-dimensional cardiac tissue models as new approach methodologies that enable in vitro proarrhythmic risk assessment with high precision of quantitative metrics for understanding clinically relevant cardiotoxicity.

2.
Occup Med (Lond) ; 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38876984

ABSTRACT

BACKGROUND: Previous studies have suggested that firefighters, police officers and civil servants in the education sector, particularly in Western countries, are vulnerable to mental stress and disorders; however, evidence for this association in South Korea is lacking. AIMS: This study aimed to identify whether firefighters, police officers and teachers are at a higher risk for occupational mental health disorders. METHODS: We used workers' compensation claims from civil servants (2009-18). Our target population comprised 46 209 civil servants (9009 civil servants in administrative and technical positions, 23 107 police officers, 4417 firefighters and 8676 civil servants in the educational sector). Occupational and environmental medicine physicians and medical doctors defined and confirmed mental disorders. We conducted Cox proportional hazards regression analyses to evaluate civil servants' risk of occupational mental health disorders. RESULTS: Compared with the civil servants in administrative and technical positions, civil servants in the education sector (hazard ratio [HR] = 2.16; 95% confidence interval [CI]:1.65-2.84) showed a statistically significant increased risk of mental disorders; conversely, firefighters did not (HR = 0.80; 95% CI 0.51-1.27). Police officers had a significantly decreased mental disorder risk compared with civil servants in administrative and technical positions (HR = 0.17; 95% CI 0.11-0.25). CONCLUSIONS: The risk of occupational mental health disorders was higher in civil servants in the education sector but lower in police officers and firefighters than civil servants in administrative and technical positions. Further studies on civil servants' mental health awareness are required to confirm our results.

3.
BJU Int ; 2024 May 26.
Article in English | MEDLINE | ID: mdl-38797721

ABSTRACT

OBJECTIVES: To address the paucity of literature comparing outcomes achieved with utilisation of the high-power holmium:yttrium-aluminium-garnet (Ho:YAG) laser with MOSES technology vs those achieved with the thulium fibre laser (TFL) in mini-percutaneous nephrolithotomy (PCNL). METHODS: A retrospective review was performed of patients undergoing supine mini-PCNL between August 2021 and May 2023. Exclusion criteria were urinary diversion, simultaneous utilisation of >1 laser platform, use of any other form of fragmentation, and ureteric stones. The Ho:YAG platform (Lumenis Pulse P120H™ with MOSES technology, 120W; Boston Scientific®) and the TFL (Soltive SuperPulsed Thulium Fibre [SPTF], 60W; Olympus®) were compared. Data on stone-free rate (SFR) were determined by computed tomography performed on the first postoperative day and presented as absence of stone fragments, no fragments larger than 2 mm, or no fragments larger than 4 mm. RESULTS: A total of 100 patients met the inclusion criteria, 51 mini-PCNLs with the Ho:YAG laser and 49 with the SPTF laser. No significant differences in demographics or stone characteristics were detected between the two groups. The Ho:YAG laser utilised less energy and time, resulting in higher ablation efficiency (P < 0.05) and less total operating time (P < 0.05). Overall, there was no difference in SFR in any category between the Ho:YAG group and the SPTF group (no fragments: relative risk [RR] 0.81, 95% confidence interval [CI] 0.59-1.12, P = 0.21; fragments <2 mm: RR 0.86, 95% CI 0.67-1.10, P = 0.23; fragments <4 mm: RR 0.96, 95% CI 0.80-1.15, P = 0.67). CONCLUSIONS: Although we observed an equivalent postoperative SFR, this study supports a shorter operating time and greater intra-operative laser efficiency with the Ho:YAG laser over the SPTF laser in mini-PCNL.

4.
Plant Biol (Stuttg) ; 25(6): 915-923, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37338124

ABSTRACT

Reactive oxygen species (ROS) cause damage to various cellular processes in almost all organisms, in particular photosynthetic organisms that depend on the electron transfer chain for CO2 fixation. However, the detoxifying process to mitigate ROS damage has not been studied intensively in microalgae. Here, we characterized the ROS detoxifying role of a bZIP transcription factor, BLZ8, in Chlamydomonas reinhardtii. To identify downstream targets of BLZ8, we carried out comparative genome-wide transcriptomic profiling of BLZ8 OX and its parental CC-4533 under oxidative stress conditions. Luciferase reporter activity assays and RT-qPCR were performed to test whether BLZ8 regulates downstream genes. We performed an in silico functional gene network analysis and an in vivo immunoprecipitation assay to identify the interaction between downstream targets of BLZ8. Comparative transcriptomic analysis and RT-qPCR revealed that overexpression of BLZ8 increased the expression levels of plastid peroxiredoxin1 (PRX1) and ferredoxin-5 (FDX5) under oxidative stress conditions. BLZ8 alone could activate the transcriptional activity of FDX5 and required bZIP2 to activate transcriptional activity of PRX1. Functional gene network analysis using FDX5 and PRX1 orthologs in A. thaliana suggested that these two genes were functionally associated. Indeed, our immunoprecipitation assay revealed the physical interaction between PRX1 and FDX5. Furthermore, the complemented strain, fdx5 (FDX5), recovered growth retardation of the fdx5 mutant under oxidative stress conditions, indicating that FDX5 contributes to oxidative stress tolerance. These results suggest that BLZ8 activates PRX1 and FDX5 expression, resulting in the detoxification of ROS to confer oxidative stress tolerance in microalgae.


Subject(s)
Chlamydomonas reinhardtii , Ferredoxins , Ferredoxins/genetics , Ferredoxins/metabolism , Chlamydomonas reinhardtii/genetics , Chlamydomonas reinhardtii/metabolism , Reactive Oxygen Species/metabolism , Peroxiredoxins/genetics , Peroxiredoxins/metabolism , Oxidative Stress
5.
Hernia ; 27(3): 593-599, 2023 06.
Article in English | MEDLINE | ID: mdl-36633705

ABSTRACT

PURPOSE: Complications of incisional hernia are amongst the commonest presentations to the emergency surgical take. Outcomes from emergency hernia repair are poor, particularly for those with complex defects and for the growing population of comorbid, high-risk patients. Attempts to avoid emergency surgery by improving success rates of non-operative management could prove hugely beneficial. Botulinum toxin A (Botox) is already used in the elective management of incisional hernia and this study evaluates if the relaxation produced could be used to augment the outcomes of conservative management of acutely presenting incisional hernia. METHODS: Patients presenting between October 2020 and April 2022 without evidence of visceral ischaemia, who had been selected for a non-operative approach, were given 300 units of Botox under image guidance to the abdominal wall in addition to standard conservative measures. RESULTS: Twelve patients were eligible for Botox administration. Median age was 75 years and median BMI was 36.45 kg/m2. All patients were high risk; minimum ASA score was 3, and median frailty score was 5. In ten patients, symptoms resolved following Botox allowing for discharge without further complication. Seven subsequently referred on to the abdominal wall team. Symptoms did not settle in the two remaining patients; one required emergency laparotomy and the second was palliated. CONCLUSION: Botox may be a useful adjunct to established non-operative measures in patients with acute presentations of incisional hernia. It may improve the acute symptoms, eliminate the need for high-risk emergency surgery, or provide a bridge to abdominal wall reconstruction.


Subject(s)
Abdominal Wall , Botulinum Toxins, Type A , Hernia, Ventral , Incisional Hernia , Humans , Aged , Incisional Hernia/surgery , Hernia, Ventral/drug therapy , Hernia, Ventral/surgery , Botulinum Toxins, Type A/therapeutic use , Herniorrhaphy/adverse effects , Herniorrhaphy/methods , Abdominal Wall/surgery , Surgical Mesh
6.
J Laryngol Otol ; 137(8): 866-872, 2023 Aug.
Article in English | MEDLINE | ID: mdl-36217672

ABSTRACT

BACKGROUND: This study primarily assessed ENT surgical trainees' preferences for the qualities of disposable and reusable fibre-optic nasendoscopes. Secondary aims included eliciting trainees' views on ENT surgery and climate change, and creating a single-centre per-use cost analysis for disposable and reusable fibre-optic nasendoscopes. METHODS: A cross-sectional study was formulated. An online survey consisting of multiple-choice and Likert-scale questions was distributed nationally. Cost analysis was performed using 2021-2022 data from the host institution. RESULTS: Twenty-four trainees responded. Data on disposable fibre-optic nasendoscopes showed no difference in overall satisfaction (p = 0.244). Reusable fibre-optic nasendoscopes had a lower cost per use compared with disposable nasendoscopes at 5 years (4.7 per cent reduction) and 10 years (7.1 per cent reduction). Of the trainees, 79.2 per cent were supportive of climate-friendly initiatives within ENT surgery, and 25 per cent felt supported by their departments. CONCLUSION: Trainees' satisfaction with disposable and reusable fibre-optic nasendoscopes is similar. Cost analysis favours reusable fibre-optic nasendoscopes in the long term at the host institution. Empowering departments and trainees to pursue climate-friendly initiatives should be encouraged.


Subject(s)
Disposable Equipment , Equipment Reuse , Humans , Cross-Sectional Studies , Costs and Cost Analysis , United Kingdom
7.
Occup Med (Lond) ; 73(1): 49-52, 2023 02 14.
Article in English | MEDLINE | ID: mdl-36282619

ABSTRACT

We describe the case of a 52-year-old male who presented with two episodes of acute exacerbations (AE) of chronic obstructive pulmonary disease (COPD) during work, while suspending live chickens for slaughter. The patient was exposed to high levels of bioaerosols, including endotoxins and microorganisms. Endotoxins can induce bronchoconstriction and airway inflammation, and COPD patients are more vulnerable to airway infections caused by microorganisms inhaled with bioaerosols. This study suggests that a high level of bioaerosols may induce airway infections, resulting in acute exacerbations of COPD.


Subject(s)
Abattoirs , Pulmonary Disease, Chronic Obstructive , Male , Humans , Animals , Chickens , Pulmonary Disease, Chronic Obstructive/complications , Disease Progression
8.
J Laryngol Otol ; 137(6): 622-628, 2023 Jun.
Article in English | MEDLINE | ID: mdl-35912870

ABSTRACT

OBJECTIVE: This study aimed to assess the effectiveness of an ENT simulation course for equipping foundation doctors with core ENT skills in preparation for an ENT senior house officer post. METHOD: A total of 41 foundation doctors in the East of England participated in our two-part simulation course. Pre- and post-course surveys, consisting of Likert scales and a Dundee Ready Educational Environment Measure, were sent to assess confidence in core ENT skills and acceptability of course format. RESULTS: Post-simulation, confidence improved in all core ENT skills taught (p < 0.001), along with confidence and preparedness to work as an ENT senior house officer (p < 0.001). Overall course median Dundee Ready Educational Environment Measure score was 48, and 100 per cent of participants would recommend this course to colleagues. CONCLUSION: Simulation improves foundation doctors' confidence in core ENT skills and increases preparedness for working as an ENT senior house officer. Guidance on core ENT skills requirements should be made available to improve uniformity amongst ENT simulation courses.


Subject(s)
Otolaryngology , Humans , Otolaryngology/education , Clinical Competence , Medical Staff, Hospital/education , Curriculum , England , Surveys and Questionnaires , Teaching
9.
Eur Rev Med Pharmacol Sci ; 26(16): 5844-5856, 2022 08.
Article in English | MEDLINE | ID: mdl-36066160

ABSTRACT

OBJECTIVE: Mycoplasma pneumoniae (M. pneumoniae) pneumonia is the second-most common cause of community-acquired pneumonia (CAP). This study aimed at investigating into the prevalence of macrolide-resistant M. pneumoniae (MRMP) with respiratory virus co-infection and the antibiotic prescriptions in children with CAP in four provinces in Korea, and to assess the variations in the findings across regions and throughout the year. PATIENTS AND METHODS: This prospective study was conducted in 29 hospitals in Korea between July 2018 and June 2020. Among the enrolled 1,063 children with CAP, all 451 patients with M. pneumoniae underwent PCR assays of M. pneumoniae and respiratory viruses, and the presence of point mutations of residues 2063 and 2064 was evaluated. RESULTS: Gwangju-Honam (88.6%) showed the highest prevalence of MRMP pneumonia, while Daejeon-Chungcheong (71.3%) showed the lowest, although the differences in prevalence were not significant (p=0.074). Co-infection of M. pneumoniae pneumonia and respiratory virus was observed in 206 patients (45.4%), and rhinovirus co-infection (101 children; 22.2%) was the most frequent. The prevalence of MRMP pneumonia with respiratory virus co-infection and the antibiotic prescriptions differed significantly among the four provinces (p < 0.05). The monthly rate of MRMP pneumonia cases among all cases of M. pneumoniae pneumonia and tetracycline or quinolone prescriptions did not differ significantly among the four regions (trend p > 0.05) during the study period. CONCLUSIONS: The prevalence of M. pneumoniae pneumonia with virus co-infection and antibiotic prescriptions could differ according to region, although the MRMP pneumonia rate showed no difference within Korea.


Subject(s)
Coinfection , Community-Acquired Infections , Pneumonia, Mycoplasma , Virus Diseases , Viruses , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Child , Coinfection/complications , Coinfection/drug therapy , Coinfection/epidemiology , Drug Resistance, Bacterial , Humans , Macrolides/therapeutic use , Mycoplasma pneumoniae/genetics , Pneumonia, Mycoplasma/drug therapy , Pneumonia, Mycoplasma/epidemiology , Prescriptions , Prospective Studies , Virus Diseases/drug therapy
10.
Eur Rev Med Pharmacol Sci ; 26(5): 1743-1752, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35302224

ABSTRACT

OBJECTIVE: This study aimed to investigate whether the lactate-to-albumin ratio (LAR) can predict mortality in patients with sepsis or septic shock. PATIENTS AND METHODS: A systematic search of the PubMed, EMBASE, Web of Science, and Google Scholar databases was conducted on December 16, 2021, for relevant articles that provided the predictive performance of LAR for mortality in patients with sepsis or septic shock. RESULTS: Eight studies encompassing a total of 4,723 patients were included in this paper. The pooled sensitivity, specificity, and diagnostic odds ratio of the LAR for predicting mortality were 0.71 (95% confidence interval [CI]: 0.54-0.84), 0.68 (95% CI: 0.58-0.76) and 5.23 (95% CI: 2.62-10.45), respectively. The area under the summary receiver operating characteristic curve was 0.74 (95% CI: 0.70-0.78). CONCLUSIONS: The current evidence suggests that LAR is moderately predictive of mortality among patients with sepsis or septic shock and may be beneficial to identify high-risk patients.


Subject(s)
Sepsis , Shock, Septic , Albumins , Humans , Lactic Acid , ROC Curve , Sepsis/diagnosis , Shock, Septic/diagnosis
13.
Eur Rev Med Pharmacol Sci ; 25(11): 4051-4063, 2021 06.
Article in English | MEDLINE | ID: mdl-34156683

ABSTRACT

OBJECTIVE: Buerger's disease is a rare disease that causes critical limb ischemia; however, the underlying pathophysiological mechanism remains unclear. Therefore, we investigated the interaction between interleukin (IL)-17 and high-mobility group protein B 1 (HMGB1) and determined whether A disintegrin and metalloproteinase 10 (ADAM10) inhibit this interaction. PATIENTS AND METHODS: The study population included 15 patients with Buerger's disease and 10 healthy donors without a history of giving peripheral blood samples. Cytokine levels were measured using a luminex multiplex assay in plasma. Flow cytometry was used to analyze the subtypes of helper T (Th) cells among peripheral blood mononuclear cells (PBMCs). The effect of ADAM10 on PBMCs was analyzed in vitro. RESULTS: The levels of inflammatory cytokines and production of pathogenic Th cells were found to be higher in Korean patients with Buerger's disease. IL-17 treatment induced HMGB1 associated molecules. HMGB1 also induced IL-17 and Th17 associated transcription factors in Buerger's patients. We observed that ADAM10 regulates the interaction between IL-17 and HMGB1 via advanced glycation end products (RAGE)/nuclear factor-kappa B (NF-kB) pathway in patients with Buerger's disease. CONCLUSIONS: This study suggests that IL-17 and HMGB1 cytokines contribute to the pathogenesis of Buerger's disease. These results indicate that ADAM10 alleviates inflammation in Buerger's disease via the HMGB1 and RAGE/NF-κB signaling pathway and provides insights into the molecular basis of and a potential therapeutic strategy for Buerger's disease.


Subject(s)
Cytokines/immunology , HMGB1 Protein/immunology , Thromboangiitis Obliterans/immunology , ADAM10 Protein/immunology , Adult , Amyloid Precursor Protein Secretases/immunology , Cells, Cultured , Cytokines/blood , Cytokines/genetics , Female , HMGB1 Protein/blood , HMGB1 Protein/genetics , Humans , Leukocytes, Mononuclear/immunology , Male , Membrane Proteins/immunology , Middle Aged , NF-kappa B/immunology , Nuclear Receptor Subfamily 1, Group F, Member 3/genetics , Receptor for Advanced Glycation End Products/genetics , Thromboangiitis Obliterans/blood , Thromboangiitis Obliterans/genetics
14.
AJNR Am J Neuroradiol ; 42(4): 681-687, 2021 04.
Article in English | MEDLINE | ID: mdl-33509919

ABSTRACT

BACKGROUND AND PURPOSE: Nigrostriatal dopaminergic function in patients with Parkinson disease can be assessed using 123I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropan dopamine transporter (123I-FP-CIT) SPECT, and a good correlation has been demonstrated between nigral status on SWI and dopaminergic denervation on 123I-FP-CIT SPECT. Here, we aim to correlate quantified dopamine transporter attenuation on 123I-FP-CIT SPECT with nigrosome-1 status using susceptibility map-weighted imaging (SMWI). MATERIALS AND METHODS: Between May 2017 and January 2018, consecutive patients with idiopathic Parkinson disease (n = 109) and control participants (n = 29) who underwent 123I-FP-CIT SPECT with concurrent 3T SWI were included. SMWI was generated from SWI. Two neuroradiologists evaluated nigral hyperintensity from nigrosome-1 on each side of the substantia nigra. Using consensus reading, we compared the 123I-FP-CIT-specific binding ratio according to nigral hyperintensity status and the 123I-FP-CIT specific binding ratio threshold to confirm the loss of nigral hyperintensity was determined using receiver operating characteristic curve analysis. RESULTS: The concordance rate between SMWI and 123I-FP-CIT SPECT was 65.9%. The 123I-FP-CIT-specific binding ratios in the striatum, caudate nucleus, and putamen were significantly lower when nigral hyperintensity in the ipsilateral substantia nigra was absent than when present (all, P < .001). The 123I-FP-CIT-specific binding ratio threshold values for the determination of nigral hyperintensity loss were 2.56 in the striatum (area under the curve, 0.890), 3.07 in the caudate nucleus (0.830), and 2.36 in the putamen (0.887). CONCLUSIONS: Nigral hyperintensity on SMWI showed high positive predictive value and low negative predictive value with dopaminergic degeneration on 123I-FP-CIT SPECT. In patients with Parkinson disease, the loss of nigral hyperintensity is prominent in patients with lower striatal specific binding ratios.


Subject(s)
Parkinsonian Disorders , Substantia Nigra , Aged , Aged, 80 and over , Denervation , Dopamine Plasma Membrane Transport Proteins , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Parkinsonian Disorders/diagnostic imaging , Substantia Nigra/diagnostic imaging , Tomography, Emission-Computed, Single-Photon
15.
AJNR Am J Neuroradiol ; 41(12): 2320-2326, 2020 12.
Article in English | MEDLINE | ID: mdl-33060104

ABSTRACT

BACKGROUND AND PURPOSE: Transoral robotic surgery is an emerging strategy for treating human papillomavirus-positive cancers, but the role of MR imaging in predicting the surgical outcome has not been established. We aimed to identify preoperative MR imaging characteristics that predispose the outcome of transoral robotic surgery toward an insecure (positive or close) surgical margin in human papillomavirus-positive tonsillar squamous cell carcinoma. MATERIALS AND METHODS: Between December 2012 and May 2019, sixty-nine patients underwent transoral robotic surgery at our institution. Among these, 29 who were diagnosed with human papillomavirus-positive tonsillar squamous cell carcinoma, did not receive neoadjuvant treatment, underwent preoperative 3T MR imaging, and had postoperative pathologic reports and were included in this retrospective study. Two neuroradiologists evaluated the preoperative MR imaging scans to determine the tumor spread through the pharyngeal constrictor muscle using a 5-point scale: 1, normal constrictor; 2, bulging constrictor; 3, thinning constrictor; 4, obscured constrictor; and 5, tumor protrusion into the parapharyngeal fat. The risk of an insecure surgical margin (involved or <1 mm) according to the MR imaging scores was predicted using logistic regression with the Firth correction. RESULTS: The interobserver agreement for the MR imaging scores was excellent (κ = 0.955, P < .001). A score of ≥4 could predict an insecure margin with 87.5% sensitivity and 92.3% specificity (area under the curve = 0.899) and was the only significant factor associated with an insecure margin in the multivariable analysis (OR, 6.59; 95% CI, 3.11-22.28; P < .001). CONCLUSIONS: The pre-transoral robotic surgery MR imaging scoring system for the pharyngeal constrictor muscle is a promising predictor of the surgical margin in human papillomavirus-positive tonsillar squamous cell carcinoma.


Subject(s)
Carcinoma, Squamous Cell/diagnostic imaging , Carcinoma, Squamous Cell/surgery , Margins of Excision , Tonsillar Neoplasms/diagnostic imaging , Tonsillar Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/virology , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Muscles/diagnostic imaging , Muscles/pathology , Papillomavirus Infections/complications , Retrospective Studies , Robotic Surgical Procedures/methods , Surgery, Computer-Assisted/methods , Tonsillar Neoplasms/virology , Treatment Outcome
16.
Sci Rep ; 10(1): 9262, 2020 06 05.
Article in English | MEDLINE | ID: mdl-32504000

ABSTRACT

Charcot-Marie-Tooth (CMT) is a group of inherited diseases clinically and genetically heterogenous, characterised by length dependent degeneration of axons of the peripheral nervous system. A missense mutation (p.R158H) in the pyruvate dehydrogenase kinase 3 gene (PDK3) has been identified as the genetic cause for an X-linked form of CMT (CMTX6) in two unrelated families. PDK3 is one of four PDK isoenzymes that regulate the activity of the pyruvate dehydrogenase complex (PDC). The balance between kinases (PDKs) and phosphatases (PDPs) determines the extend of oxidative decarboxylation of pyruvate to generate acetyl CoA, critically linking glycolysis and the energy producing Krebs cycle. We had shown the p.R158H mutation causes hyperactivity of PDK3 and CMTX6 fibroblasts show hyperphosphorylation of PDC, leading to reduced PDC activity and ATP production. In this manuscript we have generated induced pluripotent stem cells (iPSCs) by re-programming CMTX6 fibroblasts (iPSCCMTX6). We also have engineered an isogenic control (iPSCisogenic) and demonstrated that genetic correction of the p.R158H mutation reverses the CMTX6 phenotype. Patient-derived motor neurons (MNCMTX6) show increased phosphorylation of the PDC, energy metabolism defects and mitochondrial abnormalities, including reduced velocity of trafficking mitochondria in the affected axons. Treatment of the MNCMTX6 with a PDK inhibitor reverses PDC hyperphosphorylation and the associated functional deficits founds in the patient motor neurons, demonstrating that the MNCMTX6 and MNisogenic motor neurons provide an excellent neuronal system for compound screening approaches to identify drugs for the treatment of CMTX6.


Subject(s)
Charcot-Marie-Tooth Disease/genetics , Energy Metabolism/genetics , Induced Pluripotent Stem Cells/cytology , Mitochondria/pathology , Motor Neurons/pathology , Mutation , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics , Adenosine Triphosphate/metabolism , Base Sequence , Cell Differentiation/genetics , Charcot-Marie-Tooth Disease/pathology , Fibroblasts/pathology , Humans , Phosphorylation
17.
Eur J Neurol ; 27(10): 2079-2088, 2020 10.
Article in English | MEDLINE | ID: mdl-32478888

ABSTRACT

BACKGROUND AND PURPOSE: Hidden hearing loss has been reported in patients with Charcot-Marie-Tooth (CMT) disease; however, the auditory-processing deficits have not been widely explored. We investigated the psychoacoustic and neurophysiological aspects of auditory processing in patients with CMT disease type 1A (CMT1A) and type 2A (CMT2A). METHODS: A total of 43 patients with CMT1A and 15 patients with CMT2A were prospectively enrolled. All patients with CMT disease had normal sound-detection ability by using pure-tone audiometry. Spectral-ripple discrimination, temporal modulation detection and auditory frequency-following response were compared between CMT1A, CMT2A and control groups. RESULTS: Although all participants had normal audiograms, patients with CMT disease had difficulty understanding speech in noise. The psychoacoustic auditory processing was somewhat different depending on the underlying pathophysiology of CMT disease. Patients with CMT1A had degraded auditory temporal and spectral processing. Patients with CMT2A had no reduced spectral resolution, but they showed further reduced temporal resolution than the patients with CMT1A. The amplitudes of the frequency-following response were reduced in patients with CMT1A and CMT2A, but the neural timing remained relatively intact. CONCLUSIONS: When we first assessed the neural representation to speech at the brainstem level, the grand average brainstem responses were reduced in both patients with CMT1A and CMT2A compared with healthy controls. As the psychoacoustic aspects of auditory dysfunctions in CMT1A and CMT2A were somewhat different, it is necessary to consider future auditory rehabilitation methods based on their pathophysiology.


Subject(s)
Charcot-Marie-Tooth Disease , Auditory Perception , Charcot-Marie-Tooth Disease/complications , Humans , Neurophysiology , Psychoacoustics
18.
AJNR Am J Neuroradiol ; 41(3): 424-429, 2020 03.
Article in English | MEDLINE | ID: mdl-32029473

ABSTRACT

BACKGROUND AND PURPOSE: The long scan time of MR imaging is a major drawback limiting its clinical use in neuroimaging; therefore, we aimed to investigate the clinical feasibility of a 1-minute full-brain MR imaging using a multicontrast EPI sequence on a different MR imaging scanner than the ones previously reported. MATERIALS AND METHODS: We retrospectively reviewed the records of 146 patients who underwent a multicontrast EPI sequence, including T1-FLAIR, T2-FLAIR, T2WI, DWI, and T2*WI sequences. Two attending neuroradiologists assessed the image quality of each sequence to compare the multicontrast EPI sequence with routine MR imaging protocols. We used the Wilcoxon signed rank test and McNemar test to compare the 2 MR imaging protocols. RESULTS: The multicontrast EPI sequence generally showed sufficient image quality of >2 points using a 4-point assessment scale. Regarding image quality and susceptibility artifacts, there was no significant difference between the multicontrast EPI sequence DWI and routine DWI (P > .05), attesting to noninferiority of the multicontrast EPI, whereas there were significant differences in the other 4 sequences between the 2 MR imaging protocols. CONCLUSIONS: The multicontrast EPI sequence showed sufficient image quality for clinical use with a shorter scan time; however, it was limited by inferior image quality and frequent susceptibility artifacts compared with routine brain MR imaging. Therefore, the multicontrast EPI sequence cannot completely replace the routine MR imaging protocol at present; however, it may be a feasible option in specific clinical situations such as screening, time-critical diseases or for use with patients prone to motion.


Subject(s)
Brain/diagnostic imaging , Echo-Planar Imaging/methods , Image Processing, Computer-Assisted , Magnetic Resonance Imaging/methods , Neuroimaging/methods , Adolescent , Adult , Aged , Aged, 80 and over , Artifacts , Female , Humans , Male , Middle Aged , Retrospective Studies , Time Factors , Young Adult
19.
Trends Endocrinol Metab ; 30(6): 384-395, 2019 06.
Article in English | MEDLINE | ID: mdl-31076221

ABSTRACT

Polyphenols are nonessential phytonutrients abundantly found in fruits and vegetables. A wealth of data from preclinical models and clinical trials consistently supports cardiometabolic benefits associated with dietary polyphenols in murine models and humans. Furthermore, a growing number of studies have shown that specific classes of polyphenols, such as proanthocyanidins (PACs) and ellagitannins, as well as the stilbenoid resveratrol, can alleviate several features of the metabolic syndrome. Moreover, mounting evidence points to the gut microbiota as a key mediator of the health benefits of polyphenols. In this review we summarize recent findings supporting the beneficial potential of polyphenols against cardiometabolic diseases, with a focus on the role of host-microbe interactions.


Subject(s)
Cardiovascular Diseases/metabolism , Polyphenols/metabolism , Animals , Gastrointestinal Microbiome/physiology , Humans , Hydrolyzable Tannins/metabolism , Proanthocyanidins/metabolism , Resveratrol/metabolism
20.
Anaesthesia ; 74(8): 1033-1040, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31106853

ABSTRACT

Phase lag entropy, an electro-encephalography-based hypnotic depth indicator, calculates diversity in temporal patterns of phase relationship. We compared the performance of phase lag entropy with the bispectral index™ in 30 patients scheduled for elective surgery. We initiated a target-controlled infusion of propofol using the Schnider model, and assessed sedation levels using the Modified Observer's Assessment of Alertness/Sedation scale every 30 s with each stepwise increase in the effect-site propofol concentration. Phase lag entropy and bispectral index values were recorded. The correlation coefficient and prediction probability between phase lag entropy or bispectral index and the sedation level or effect-site propofol concentration were analysed. We calculated baseline variabilities of phase lag entropy and bispectral index. In addition, we applied a non-linear mixed-effects model to obtain the pharmacodynamic relationships among the effect-site propofol concentration, phase lag entropy or bispectral index and sedation level. As sedation increased, phase lag entropy and bispectral index both decreased. The prediction probability values of phase lag entropy and bispectral index for sedation levels were 0.697 and 0.700 (p = 0.261) and for the effect-site concentration of propofol were 0.646 and 0.630 (p = 0.091), respectively. Baseline variability in phase lag entropy and bispectral index was 3.3 and 5.7, respectively. The predicted propofol concentrations, using the Schnider pharmacokinetic model, producing a 50% probability of moderate and deep sedation were 1.96 and 3.01 µg.ml-1 , respectively. Phase lag entropy was found to be useful as a hypnotic depth indicator in patients receiving propofol sedation.


Subject(s)
Conscious Sedation , Entropy , Hypnotics and Sedatives/pharmacology , Propofol/pharmacology , Adult , Aged , Electroencephalography , Female , Humans , Logistic Models , Male , Middle Aged
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