Epithelial sodium channel (ENaC) is an amiloride-sensitive sodium ion channel that is expressed in epithelial tissues. ENaC overexpression and/or hyperactivation in airway epithelial cells cause ...sodium over-absorption and dysregulated ciliary movement for mucus clearance; however, the agents that suppress constitutive airway ENaC activation are yet to be clinically available. Here, we focused on macrolides, which are widely used antibiotics that have many potential immunomodulatory effects. We examined whether macrolides could modulate constitutive ENaC activity and downstream events that typify cystic fibrosis (CF) and chronic obstructive pulmonary diseases (COPD) in in vitro and in vivo models of ENaC overexpression. Treatment of ENaC-overexpressing human bronchial epithelial cells (β/γENaC-16HBE14o- cells) with three macrolides (erythromycin, clarithromycin, azithromycin) confirmed dose-dependent suppression of ENaC function. For in vivo studies, mice harboring airway specific βENaC overexpression (C57BL/6J-βENaC-transgenic mice) were treated orally with azithromycin, a well-established antimicrobial agent that has been widely prescribed. Azithromycin treatment modulated pulmonary mechanics, emphysematous phenotype and pulmonary dysfunction. Notably, a lower dose (3 mg kg−1) of azithromycin significantly increased forced expiratory volume in 0.1 s (FEV0.1), an inverse indicator of bronchoconstriction. Although not statistically significant, improvement of pulmonary obstructive parameters such as emphysema and lung dysfunction (FEV0.1%) was observed. Our results demonstrate that macrolides directly attenuate constitutive ENaC function in vitro and may be promising for the treatment of obstructive lung diseases with defective mucociliary clearance, possibly by targeting ENaC hyperactivation.
Purpose
Using the multi-detector computed tomography and related three-dimensional imaging technology, we developed a vertebral needle targeting simulation training system named spinal needling ...intervention practice using ray-summation imaging (SNIPURS). Herein, we assessed the utility of SNIPURS by evaluating changes in the learning curves of SNIPURS trainees.
Methods
Twenty-one examinees were enrolled: seven experienced operators (expert group), seven trainees with coaching (coaching group), and seven trainees without coaching (non-coaching group). They performed six tests of vertebral needle targeting simulation on the workstation-generated spinal ray-summation images of six patients with vertebral fractures. In each test, they determined the bilateral trans-pedicular puncture points and angles on two thoracic and two lumbar vertebrae on ray-summation imaging (i.e., 8 simulations per test). The coaching group received coaching by a trainer after Tests 1 and 4, while the others did not. Scores were given based on the trans-pedicular pathway (1 point) or not (0 point). Eight virtual needles were evaluated in each of Tests 1–6.
Results
Among the three groups, the expert group had the highest average scores on Tests 1–4 (expert: 3.86, 6.57, 7.43, and 7.57; coaching: 1.86, 6.14, 6, and 6.29; and non-coaching: 1.14, 4.14, 4.71, and 4.86). The coaching group’s scores caught up with the expert groups’ average scores on Tests 5 and 6, whereas those of the non-coaching group did not (expert and coaching: 7.86 and 8.00, non-coaching: 5.86 and 7.14). All examinees in the expert and coaching groups achieved a perfect score on the final Test 6, whereas three of the seven non-coaching trainees did not.
Conclusion
SNIPURS might be suitable for vertebral needle targeting training. The coaching provided during SNIPURS training helped the trainees to acquire the spinal puncture techniques in PVP.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the world, and has no radical treatment. Inhibition of amiloride-sensitive epithelial sodium ion channel (ENaC) ...has now been considered as a potential therapeutic target against COPD. One possible modulator of ENaC is AMP-activated protein kinase (AMPK), a key molecule that controls a wide variety of cellular signals; however, little is known about whether metformin, a clinically available AMPK activator, has a protective role against ENaC-associated chronic pulmonary phenotypes, such as emphysema and pulmonary dysfunction. We first used ENaC-overexpressing human bronchial epithelial cells (β/γENaC-16HBE14o-) and identified that Metformin significantly reduced ENaC activity. Consistently, in vivo treatment of ENaC-overexpressing COPD mouse model (C57BL/6-βENaC-Tg mice) showed improvement of emphysema and pulmonary dysfunction, without any detrimental effect on non-pulmonary parameters (blood glucose level etc.). Bronchoalveolar lavage fluid (BALF) and lung tissue analyses revealed significant suppression in the infiltration of neutrophils as well as the expression of inflammatory markers (KC), neutrophil gelatinase (MMP9) and macrophage elastase (MMP12) in metformin-treated C57BL/6-βENaC-Tg mice. Overall, the present study demonstrates that metformin directly inhibits ENaC activity in vitro and provides the first evidence of therapeutical benefit of Metformin for COPD with higher ENaC activity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cystic fibrosis (CF) is a hereditary disease typically characterized by infection-associated chronic lung inflammation. The persistent activation of toll-like receptor (TLR) signals is considered one ...of the mechanisms for the CF hyperinflammatory phenotype; however, how negative regulatory signals of TLRs associate with CF inflammation is still elusive. Here, we showed that the cell surface expression of a single immunoglobulin interleukin-1 receptor (IL-1R)-related molecule (SIGIRR), a membrane protein essential for suppressing TLRs- and IL-1R-dependent signals, was remarkably decreased in CF airway epithelial cells compared to non-CF cells. Notably, CF airway epithelial cells specifically and highly expressed a unique, alternative splice isoform of the SIGIRR that lacks exon 8 (Δ8-SIGIRR), which results in the production of a C-terminal truncated form of the SIGIRR. Δ8-SIGIRR was expressed intracellularly, and its over-expression abolished the cell surface expression and function of the full-length SIGIRR (WT-SIGIRR), indicating its dominant-negative effect leading to the deficiency of anti-inflammatory activity in CF cells. Consistently, IL-37, a ligand for the SIGIRR, failed to suppress viral dsRNA analogue poly(I:C)-dependent JNK activation and IL-8 production, confirming the reduction in the functional WT-SIGIRR expression in the CF cells. Together, our studies reveal that SIGIRR-dependent anti-inflammatory activity is defective in CF airway epithelial cells due to the unique splicing switch of the SIGIRR gene and provides the first evidence of IL-37-SIGIRR signaling as a target of CF airway inflammation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The purpose of the current study was to investigate the biological effects of protons and photons in combination with cisplatin in cultured cells and elucidate the mechanisms responsible for their ...combined effects. To evaluate the sensitizing effects of cisplatin against X-rays and proton beams in HSG, EMT6 and V79 cells, the combination index, a simple measure for quantifying synergism, was estimated from cell survival curves using software capable of performing the Monte Carlo calculation. Cell death and apoptosis were assessed using live cell fluorescence imaging. HeLa and HSG cells expressing the fluorescent ubiquitination-based cell cycle indicator system (Fucci) were irradiated with X-rays and protons with cisplatin. Red and green fluorescence in the G1 and S/G2/M phases, respectively, were evaluated and changes in the cell cycle were assessed. The sensitizing effects of ≥1.5 μM cisplatin were observed for both X-ray and proton irradiation (P < 0.05). In the three cell lines, the average combination index was 0.82-1.00 for X-rays and 0.73-0.89 for protons, indicating stronger effects for protons. In time-lapse imaging, apoptosis markedly increased in the groups receiving ≥1.5 μM cisplatin + protons. The percentage of green S/G2/M phase cells at that time was higher when cisplatin was combined with proton beams than with X-rays (P < 0.05), suggesting more significant G2 arrest. Proton therapy plus ≥1.5 μM cisplatin is considered to be very effective. When combined with cisplatin, proton therapy appeared to induce greater apoptotic cell death and G2 arrest, which may partly account for the difference observed in the combined effects.
We investigated the efficacy and exposure to radiation in 320-detector row computed tomography fluoroscopy-guided (CTF-guided) interventions.
We analysed 231 320-detector row CTF-guided interventions ...(207 patients over 2 years and 6 months) in terms of technical success rates, clinical success rates, complications, scanner settings, overall radiation doses (dose-length product, mGy*cm), patient doses of peri-interventional CT series, and interventional CT (including CTF), as a retrospective cohort study. The relationships between patient radiation dose and interventional factors were assessed using multivariate analysis.
Overall technical success rate was 98.7% (228/231). The technical success rates of biopsies, drainages, and aspirations were 98.7% (154/156), 98.5% (66/67), and 100% (8/8), respectively. The clinical success rate of biopsies was 93.5% (146/156). All three major complications occurred in chest biopsies. The median total radiation dose was 522.4 (393.4-819.8) mGy*cm. Of the total radiation dose, 87% was applied during the pre- and post-interventional CT series. Post-interventional CT accounted for 24.4% of the total radiation dose. Only 11.4% of the dose was applied by CTF-guided intervention. Multilinear regression demonstrated that male sex, body mass index, drainage, intervention time, and helical scan as post-interventional CT were significantly associated with higher dose.
The 320-detector row CTF interventions achieved a high success rate. Dose reduction in post-interventional CT provides patient dose reduction without decreasing the technical success rates.
This is the first study on the relationship between various interventional outcomes and patient exposure to radiation in 320-detector row CTF-guided interventions, suggesting a new perspective on dose reduction.
A 78-year-old man complaining of left leg swelling was diagnosed with an abdominal aortic aneurysm with an irregular margin. A four-dimensional computed tomography (CT) showed an aortoiliac vein ...fistula. An AFX stent graft was urgently implanted, and a Viabahn VBX was inserted into the left iliac vein. The aneurysmal sac was embolized. After the procedure, enhanced CT confirmed a patent stent graft without any endoleak or fistula. The patient was discharged ambulatory. An aortoiliac vein fistula is a differential diagnosis for leg edema, and a four-dimensional CT is beneficial in diagnosing the condition.
Pulmonary emphysema, inflammation and senescence-like phenotype are pathophysiological characteristics of chronic obstructive pulmonary disease (COPD). Recently, a murine model of COPD has been ...established by inducing airway-specific overexpression of epithelial Na+ channel β subunit (βENaC-Tg mice). However, little is known about the histological and biochemical differences between βENaC-Tg mice and an existing acute emphysematous mouse model (elastase-induced model). Here, we first utilized whole lung image-based quantification method for histological analysis to determine auto-measure parameters, including alveolar area, alveolar perimeter, (major axis + minor axis)/2 and Feret diameter. Even though the extent of emphysema was similar in both models, the coefficient of variation (CV) of all histological parameters was smaller in βENaC-Tg mice, indicating that βENaC-Tg mice show homogeneous emphysema as compared with elastase-induced acute model. Expression analysis of lung tissue RNAs further revealed that elastase-induced model exhibits transient changes of inflammation markers (Kc, Il-6, Lcn2) and senescence-related markers (Sirt1, p21) at emphysema-initiation stage (1 day), which does not last until emphysema-manifestation stage (3 weeks); while the up-regulation is stable at emphysema-manifestation stage in βENaC-Tg mice (14-week old). Thus, these studies demonstrate that βENaC-Tg mice exhibit diffuse-type emphysema with stable expression of inflammatory and senescence-like markers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
To retrospectively analyze the safety and efficacy of percutaneous vertebroplasty (PVP) for patients aged 90 or over.
Materials and methods
We analyzed 130 consecutive patients with ...osteoporotic vertebral fractures who underwent a first-time PVP between May 2015 and September 2017 at our institution. We divided them into the elder patient group aged 90 years or over (
n
= 21) and the younger patient group under 90 years (
n
= 109). We compared the two groups’ background, treatments, and outcomes using univariate analyzes and the log rank test.
Results
A significant difference was observed in dementia (19% in the younger group vs. 48% in the elder group,
p
< 0.01). No significant difference was revealed in the procedure time or the rate of complications. The post-PVP mobility function and the pain level were significantly improved compared to before PVP in both groups (
p
< 0.01 each). No significant differences were observed between the two groups in the recurrence of vertebral fracture after treatment (17% vs. 14%) or the 1-year survival rate (79% vs. 86%), respectively.
Conclusion
The results of our analyzes suggested that a PVP can safely and effectively contribute to pain relief as well as the restoration of ambulation for patients aged 90 or over.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Abstract
Background
Ruptured aneurysm is a serious complication of distal pancreatectomy (DP) or pancreatoduodenectomy (PD) that can be life-threatening if not treated promptly. This study aimed to ...examine the efficacy of a Viabahn stent graft for stopping bleeding after pancreatectomy.
Methods
Between April 2016 and June 2022, we performed 245 pancreatectomies in our institution. Six patients experienced postoperative bleeding and underwent endovascular treatment.
Results
All six cases of bleeding occurred post-PD (3.7%). The bleeding was from gastroduodenal artery (GDA) pseudoaneurysms in three patients, and Viabahn stent grafts were inserted. All three patients did not show liver function abnormalities or hepatic blood flow disorders. One patient with a Viabahn stent graft experienced rebleeding, which required further management to obtain hemostasis. Of the six cases in which there was hemorrhage, one case of bleeding from the native hepatic artery could not be managed.
Conclusions
Using the Viabahn stent graft is an effective treatment option for postoperative bleeding from GDA pseudoaneurysms following PD. In most cases, using this device resulted in successful hemostasis, without observed abnormalities in hepatic function or blood flow.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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