Differentiating non-epileptic seizures from epileptic seizures in Glut1 deficiency syndrome.

AIM: To investigate the clinical characteristics of non-epileptic seizures due to transient brain dysfunction caused by energy deficiency after prolonged fasting or exercise in individuals with glucose transporter type 1 deficiency syndrome (Glut1DS), and then elucidate further the seizure features to distinguish non-epileptic seizures from epileptic seizures. METHOD: This retrospective case-control study included 57 non-epileptic seizures and 23 epileptic seizures (control group) in 14 individuals (11 males, three females; aged 5-44 years, median = 20 years) with Glut1DS, all with a heterozygous pathogenic SLC2A1 mutation. RESULTS: Non-epileptic seizures were classified as paroxysmal altered consciousness (n = 8), movement disorders (n = 35) (eye-head movements, ataxia, spasticity, weakness, involuntary movement), dysaesthesia (n = 8), and vomiting (n = 6) at the peak ages at onset of 5 to 10 years. Ketogenic diet therapy was effective in 33 of 43 (77%) non-epileptic seizures. Providing supplementary food before high-impact exercise or during attacks prevented or mitigated non-epileptic seizures in some individuals. Glut1DS-associated non-epileptic seizures are fundamentally situation-related seizures with specific provoking and ameliorating factors. Non-epileptic seizures can be distinguished from epileptic seizures by the absence of complete consciousness loss and rapid postictal recovery despite prolonged seizures. INTERPRETATION: Non-epileptic seizures are not well recognized but require different therapeutic approaches compared to epileptic seizures. Awareness of the differentiation of non-epileptic seizures from epileptic seizures is essential when performing preventive or therapeutic decision-making for acute exacerbation seizures.

Feasibility of initiating robotic surgery during the early stages of gastrointestinal surgery education.

PURPOSE: Minimally invasive surgery for gastrointestinal cancers is rapidly advancing; therefore, surgical education must be changed. This study aimed to examine the feasibility of early initiation of robotic surgery education for surgical residents. METHODS: The ability of staff physicians and residents to handle robotic surgical instruments was assessed using the da Vinci® skills simulator (DVSS). The short-term outcomes of 32 patients with colon cancer who underwent robot-assisted colectomy (RAC) by staff physicians and residents, supervised by a dual console system, between August 2022 and March 2024 were compared. RESULTS: The performances of four basic exercises were assessed after implementation of the DVSS. Residents required less time to complete these exercises and achieved a higher overall score than staff physicians. There were no significant differences in the short-term outcomes, operative time, blood loss, incidence of postoperative complications, and length of the postoperative hospital stay of the two surgeon groups. CONCLUSION: Based on the evaluation involving the DVSS and RAC results, it appears feasible to begin robotic surgery training at an early stage of surgical education using a dual console system.

Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis.

Stimulation of cells with TNFα can promote distinct cell death pathways, including RIPK1-independent apoptosis, necroptosis, and RIPK1-dependent apoptosis (RDA)-the latter of which we still know little about. Here we show that RDA involves the rapid formation of a distinct detergent-insoluble, highly ubiquitinated, and activated RIPK1 pool, termed "iuRIPK1." iuRIPK1 forms after RIPK1 activation in TNF-receptor-associated complex I, and before cytosolic complex II formation and caspase activation. To identify regulators of iuRIPK1 formation and RIPK1 activation in RDA, we conducted a targeted siRNA screen of 1,288 genes. We found that NEK1, whose loss-of-function mutations have been identified in 3% of ALS patients, binds to activated RIPK1 and restricts RDA by negatively regulating formation of iuRIPK1, while LRRK2, a kinase implicated in Parkinson's disease, promotes RIPK1 activation and association with complex I in RDA. Further, the E3 ligases APC11 and c-Cbl promote RDA, and c-Cbl is recruited to complex I in RDA, where it promotes prodeath K63-ubiquitination of RIPK1 to lead to iuRIPK1 formation. Finally, we show that two different modes of necroptosis induction by TNFα exist which are differentially regulated by iuRIPK1 formation. Overall, this work reveals a distinct mechanism of RIPK1 activation that mediates the signaling mechanism of RDA as well as a type of necroptosis.

[Brain Calcification].

Brain calcification can be either physiological or pathological. Pathological calcification occurs due to a wide spectrum of causes, including congenital disorders, infections, endocrine/metabolic diseases, cerebrovascular diseases, and neoplasms. The patient's age, localization of the calcification, and association with other imaging findings are useful for the correct diagnosis. Dural arteriovenous fistulas with cortical venous reflux should be included in the differential diagnosis of subcortical calcification via CT. MRA should be conducted subsequently. We recently reported the clinical and imaging characteristics of calcified brain metastases in 20 patients. Hemorrhage, necrosis, or degeneration were detected within the lesions in six patients. Both T1WI and T2WI showed a hyperintense mass surrounded by a hypointense rim in one patient. Hemorrhagic brain metastases can mimic cerebral cavernous malformations. Cancer metastasis should be considered as a differential diagnosis when calcified or hemorrhagic masses are detected in middle-aged and elderly patients. We recommend conducting MRI with Gd enhancement.

RIPK1 mediates a disease-associated microglial response in Alzheimer's disease.

Dysfunction of microglia is known to play an important role in Alzheimer's disease (AD). Here, we investigated the role of RIPK1 in microglia mediating the pathogenesis of AD. RIPK1 is highly expressed by microglial cells in human AD brains. Using the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model, we found that inhibition of RIPK1, using both pharmacological and genetic means, reduced amyloid burden, the levels of inflammatory cytokines, and memory deficits. Furthermore, inhibition of RIPK1 promoted microglial degradation of Aß in vitro. We characterized the transcriptional profiles of adult microglia from APP/PS1 mice and identified a role for RIPK1 in regulating the microglial expression of CH25H and Cst7, a marker for disease-associated microglia (DAM), which encodes an endosomal/lysosomal cathepsin inhibitor named Cystatin F. We present evidence that RIPK1-mediated induction of Cst7 leads to an impairment in the lysosomal pathway. These data suggest that RIPK1 may mediate a critical checkpoint in the transition to the DAM state. Together, our study highlights a non-cell death mechanism by which the activation of RIPK1 mediates the induction of a DAM phenotype, including an inflammatory response and a reduction in phagocytic activity, and connects RIPK1-mediated transcription in microglia to the etiology of AD. Our results support that RIPK1 is an important therapeutic target for the treatment of AD.

Safety and efficacy of verinurad, a selective URAT1 inhibitor, for the treatment of patients with gout and/or asymptomatic hyperuricemia in the United States and Japan: Findings from two phase II trials.

Objective: Evaluate efficacy/safety of verinurad monotherapy in patients with gout (Japan/US) or asymptomatic hyperuricemia (Japan).Methods: Two randomized, placebo-controlled, phase II studies were conducted (NCT01927198/NCT02078219). Patients were randomized to once-daily doses of placebo or escalating doses of verinurad (study 1: 5-12.5 mg; study 2: 2.5-15 mg). Primary endpoint was percentage change from baseline in serum urate (sUA) at week 12 (study 1)/week 16 (study 2). Safety was also assessed.Results: Most patients in study 1 (n = 171) were white (74.9%); all patients were Japanese in study 2 (n = 204). Least squares means (±SE) estimate of percentage change in sUA levels from baseline in study 1 was 1.2 ± 2.9 for placebo, and -17.5 ± 2.8, -29.1 ± 2.8, -34.4 ± 2.9 for verinurad 5, 10, 12.5 mg, respectively. In study 2, results were -2.4 ± 2.5 and -31.7 ± 2.5, -51.7 ± 2.6,-55.8 ± 2.5, respectively. Difference from placebo was significant for each verinurad dose (p<.0001). The proportion of patients with treatment-emergent adverse events (TEAEs) was similar across all groups. Renal-related TEAEs were more common with verinurad than placebo.Conclusion: Verinurad monotherapy resulted in sustained reductions in sUA in Japanese/US patients but renal AEs occurred, so verinurad alone is not recommended for treatment of hyperuricemia or gout. The renal consequences of excessive uric acid excretion deserve study.

Verinurad combined with febuxostat in Japanese adults with gout or asymptomatic hyperuricaemia: a phase 2a, open-label study.

Objectives: Verinurad (RDEA3170) is a high-affinity inhibitor of the URAT1 transporter in clinical development for treating gout and asymptomatic hyperuricaemia. The aim of this Phase 2a, randomized, open-label study was to investigate the multiple-dose pharmacodynamics, pharmacokinetics and safety of oral verinurad combined with febuxostat vs febuxostat alone and verinurad alone. Methods: Japanese male subjects aged 21-65 years with gout (n = 37) or asymptomatic hyperuricaemia (n = 35) and serum urate (sUA) ⩾8 mg/dl were randomized to febuxostat (10, 20, 40 mg) in combination with verinurad (2.5-10 mg), verinurad alone (2.5-15 mg), febuxostat alone (10, 20, 40 mg) or benzbromarone alone (50 mg). There were four treatment periods per cohort and each treatment period was 7 days. Study drugs were administered once-daily after breakfast. Plasma, serum and urine samples were measured at pre-set intervals on days -1, 7, 14, 21 and 28. Results: Verinurad combined with febuxostat decreased sUA in dose-dependent manner, providing greater sUA lowering than febuxostat alone at the same dose (P < 0.001). Urinary uric acid excretion rate was increased by verinurad, reduced by febuxostat and comparable to baseline for verinurad combined with febuxostat. Verinurad from 2.5 mg to 15 mg was well tolerated, with no withdrawals due to adverse events. Laboratory assessments showed no clinically meaningful changes during combination treatment. Conclusion: Verinurad combined with febuxostat decreased sUA dose-dependently while maintaining uric acid excretion similar to baseline. All dose combinations of verinurad and febuxostat were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout. Trial registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02317861.

Bilateral Cavernous Carotid Aneurysms: The Growth Potential of a Contralateral Aneurysm after Therapeutic Unilateral Internal Carotid Artery Occlusion.

BACKGROUND: Although the introduction of flow-diverter stents has been recognized as a major revolution in the treatment of cavernous carotid aneurysms (CCAs), therapeutic internal carotid artery occlusion (TICAO) remains a reliable procedure for alleviating symptoms caused by CCAs. However, TICAO has the potential risk of the enlargement of coexisting aneurysms that are frequently detected in CCA patients. The purpose of this study is to assess the occurrence of the enlargement of aneurysms coexisting with CCAs after TICAO. METHODS: We reviewed medical charts of CCA patients who were managed using unilateral TICAO. Coexisting aneurysms were identified using angiograms obtained before TICAO, and imaging data in long follow-up periods were retrospectively examined to determine the extent of the enlargement after TICAO. RESULTS: Of 12 patients with CCAs, 10 had 12 coexisting aneurysms; 5 of the coexisting aneurysms (41.7%) showed enlargement during a mean follow-up period of 8.1 years, and all enlarged aneurysms were smaller of the bilateral CCAs; the larger CCA had been managed by TICAO. Five of 6 (83.3%) patients with bilateral CCAs showed enlargement of the contralateral aneurysm after TICAO. Two contralateral CCAs showed marked enlargement after TICAO and were subsequently treated with stent-assisted coil embolization. CONCLUSIONS: Contralateral, smaller aneurysms frequently enlarge after unilateral TICAO in patients with bilateral CCAs. The findings emphasize the importance of long-term observation after TICAO and appropriate interventions against enlarging contralateral aneurysms.

[Optimal parameter decision method in VMAT for lung tumors with respiratory motions].

When performing lung cancer treatments using volumetric modulated arc therapy (VMAT) technique, dose error related to respiratory motion of tumors and multi leaf collimator (MLC) movement may occur. The dose error causes daily dose variation in multiple fractionations irradiation. The purpose of this study is to verify the influence of the respiratory motion and the MLC movement on the daily dose variation, and to confirm the feasibility of deciding robust planning parameter against the dose variation. We prepared 5 VMAT plans for imitating lung tumor in thorax dynamic phantom. Dose calculations of these plans were done taking into account the respiratory motions. We examined the relation between dose variation and two parameters that were number of respiration in an arc and MLC gap width. We presented the relationship between the dose variation and each parameters using regression analysis, and we could derive the approximation formula for estimating the dose variation using these parameters. We could estimate dose variation in another VMAT plans using the approximation formula and another plans parameters. By confirming dose variation in planning procedure using this estimation method, we may decide planning parameter taking the dose variation into account. So, we could establish the estimation method to decide adequate planning parameters in VMAT.

Assessment of Surgical Effects on Patients with Obstructive Sleep Apnea Syndrome Using Computational Fluid Dynamics Simulations.

Obstructive sleep apnea syndrome is one of the most common sleep disorders. To treat patients with this health problem, it is important to detect the severity of this syndrome and occlusion sites in each patient. The goal of this study is to test the hypothesis that the cure of obstructive sleep apnea syndrome by maxillomandibular advancement surgery can be predicted by analyzing the effect of anatomical airway changes on the pressure effort required for normal breathing using a high-fidelity, 3-D numerical model. The employed numerical model consists of: 1) 3-D upper airway geometry construction from patient-specific computed tomographic scans using an image segmentation technique, 2) mixed-element mesh generation of the numerically constructed airway geometry for discretizing the domain of interest, and 3) computational fluid dynamics simulations for predicting the flow field within the airway and the degree of severity of breathing obstruction. In the present study, both laminar and turbulent flow simulations were performed to predict the flow field in the upper airway of the selected patients before and after maxillomandibular advancement surgery. Patients of different body mass indices were also studied to assess their effects. The numerical results were analyzed to evaluate the pressure gradient along the upper airway. The magnitude of the pressure gradient is regarded as the pressure effort required for breathing, and the extent of reduction of the pressure effort is taken to measure the success of the surgery. The description of the employed numerical model, numerical results from simulations of various patients, and suggestion for future work are detailed in this paper.

[Impact of dynamic parameters on dose delivery accuracy in volumetric modulated arc therapy].

Volumetric modulated arc therapy (VMAT) is an irradiation method in which the multi-leaf collimator (MLC) shape, gantry speed and dose-rate is continuously varied. Gantry speed and dose-rate are treated as specific dynamic parameters (DPs) in VMAT, so there is a need to confirm the influence of DPs on dose distribution. The purpose of this study was to verify the impact of DPs on the accuracy of dose delivery in VMAT. We adopted an irradiation scenario in which DPs were modified from the original plan without making any changes in the dose distribution. We carried out irradiation and measured the dose distributions using a Delta4 diode array phantom, during which we acquired log files that enabled us to calculate DPs. The results showed that dose errors exceeding 1% or geometric errors greater than 1 mm were not produced by modifying the DPs. We were therefore able to verify the impact of DPs on dose delivery accuracy in VMAT.

Air inflow into vacuum-type immobilization devices impacts setup errors.

We aimed to determine the impact of air inflow into vacuum-type immobilization devices (VIDs) on setup errors. We assigned 70 patients undergoing radiotherapy for head and neck cancer to groups V (n = 34) or N (n = 36) according to whether the VIDs were deflated weekly or not deflated during treatment, respectively. We calculated systematic errors (Σ) as the standard deviations (SDs) of mean errors, and random errors (σ) as the root mean square of SDs in each patient. We compared overall means (µ), SDs (SDoverall), random errors and systematic errors. We also measured temporary pressure changes in VIDs to determine the influence of pressure changes in VIDs on setup errors. The µ was within 0.20 mm and 0.2° in both groups, whereas SDoverall significantly differed between them. The SDoverall differed the most in the Roll axes of groups N (0. 87°) and V (0.58°). The Σ and σ values were lower in all axes of group V than in group N. Despite the initial deflation target of - 70 kPa, the pressure in VIDs reached - 5 kPa at the end of treatment. However, weekly deflation apparently maintained pressure at - 20 kPa. Effective pressure control in VIDs can reduce patient-by-patient variation and improve setup reproducibility for individual patients, consequently resulting in small variations among overall setup errors.

Modeling of a tissue expander with a radiofrequency identification port in postmastectomy radiation therapy planning.

The purpose of this study was to evaluate the dose attenuation of Motiva Flora® (Flora, Establishment Labs, Alajuela, Costa Rica) tissue expander with a radiofrequency identification port locator and to develop a model for accurate postmastectomy radiation therapy planning. Dose attenuation was measured using an EBT3 film (Ashland, Bridgewater, NJ), and the optimal material and density assignment for the radiofrequency identification coil for dose calculation were investigated using the AcurosXB algorithm on the Eclipse (Varian Medical Systems, Palo Alto, CA) treatment planning system. Additionally, we performed in vivo dosimetry analysis using irradiation tangential to the Flora tissue expander to validate the modeling accuracy. Dose attenuations downstream of the Flora radiofrequency identification coil was 1.29% for a 6 MV X-ray and 0.99% for a 10 MV X-ray when the coil was placed perpendicular to the beam. The most suitable assignments for the material and density of the radiofrequency identification coil were aluminum and 2.27 g/cm3, respectively, even though the coil was actually made of copper. Gamma analysis of in vivo dosimetry with criteria of 3% and 2 mm did not fail in the coil region. Therefore, we conclude that the model is reasonable for clinical use.

Investigator-initiated clinical trial of stabilizer device: A novel intracranial exchange guidewire for neuroendovascular treatments.

BACKGROUND: Neuroendovascular procedures, especially those involving significant vessel tortuosity, giant intracranial aneurysms, or distally located lesions, frequently necessitate exchange methods. However, exchange maneuvers pose a risk of inadvertent vessel injury. To address these challenges, a Stabilizer device was developed and evaluated for its efficacy and safety. This clinical trial aimed to assess the efficacy and safety of the Stabilizer device in facilitating the navigation of neuroendovascular devices to target lesions in cases where the exchange technique was necessary. METHODS: This was a single-arm, prospective, open-label, multicenter clinical trial performed at nine different sites. It focused on investigating the use of the Stabilizer device for treating intracranial aneurysms and atherosclerosis. RESULTS: A total of 31 patients were enrolled across nine centers in Japan from July 21, 2022, to March 10, 2023. The study enrolled 24 (77.4%) patients with intracranial aneurysms and seven (22.6%) patients with intracranial artery stenosis. Majority of the target lesions were in the middle cerebral artery territory (83.9%). The Stabilizer device was used to exchange for 0.027-inch catheters, intermediate catheters, PTA balloons, and Wingspan stent system. The Stabilizer device demonstrated 100% technical success rate. While three complications related to the treatment were noted, there were no complications related to the device, including any vascular damage. CONCLUSIONS: This is the first multicenter clinical trial that investigated and demonstrated technical efficacy as well as overall safety profile of the Stabilizer device in neuroendovascular procedures where the use of an exchange method was necessary.

A cryptic microdeletion including MBD5 occurring within the breakpoint of a reciprocal translocation between chromosomes 2 and 5 in a patient with developmental delay and obesity.

The 2q23.1 deletion syndrome has been recently recognized as a neurodevelopmental disorder associated with intellectual disability, epilepsy, and autism spectrum disorder. Recently, methyl-CpG-binding domain 5 gene (MBD5), located in the 2q23.1 region, has been considered as a single causative gene of this syndrome. We report on a female patient with a de novo reciprocal translocation between chromosomes 2 and 5. Chromosomal microarray testing revealed a cryptic 896 kb deletion that included MBD5. Although clinical manifestations of this patient are compatible with those of patients with 2q23.1 deletion syndrome, a focal pachygyria revealed by brain magnetic resonance imaging has never been observed in the previously reported cases. Obesity caused by hyperphagia was observed in our patient and 28% of the previously reported patients with the 2q23.1 deletion syndrome. For better medical management, appropriate dietary guidance against hyperphagia should be given to the patients' family.

Computational fluid dynamic analysis of the posterior airway space after maxillomandibular advancement for obstructive sleep apnea syndrome.

PURPOSE: This study evaluated the soft tissue change of the upper airway after maxillomandibular advancement (MMA) using computational fluid dynamics. MATERIALS AND METHODS: Eight patients with obstructive sleep apnea syndrome who required MMA were recruited into this study. All participants underwent pre- and postoperative computed tomography and then MMA by a single oral and maxillofacial surgeon. Upper airway computed tomographic datasets for these 8 patients were created with high-fidelity 3-dimensional numerical models for computational fluid dynamics. The 3-dimensional models were simulated and analyzed to study how changes in airway anatomy affect the pressure effort required for normal breathing. Airway dimensions, skeletal changes, apnea-hypopnea index, and pressure effort of pre- and postoperative 3-dimensional models were compared and correlations were interpreted. RESULTS: After MMA, laminar and turbulent air flows were significantly decreased at every level of the airway. The cross-sectional areas at the soft palate and tongue base were significantly increased. CONCLUSIONS: This study showed that MMA increased airway dimensions by increasing the distance from the occipital base to the pogonion. An increase of this distance showed a significant correlation with an improvement in the apnea-hypopnea index and a decreased pressure effort of the upper airway. Decreasing the pressure effort will decrease the breathing workload. This improves the condition of obstructive sleep apnea syndrome.

[A practical procedure to improve the accuracy of radiochromic film dosimetry: a integration with a correction method of uniformity correction and a red/blue correction method].

It has been reported that the light scattering could worsen the accuracy of dose distribution measurement using a radiochromic film. The purpose of this study was to investigate the accuracy of two different films, EDR2 and EBT2, as film dosimetry tools. The effectiveness of a correction method for the non-uniformity caused from EBT2 film and the light scattering was also evaluated. In addition the efficacy of this correction method integrated with the red/blue correction method was assessed. EDR2 and EBT2 films were read using a flatbed charge-coupled device scanner (EPSON 10000G). Dose differences on the axis perpendicular to the scanner lamp movement axis were within 1% with EDR2, but exceeded 3% (Maximum: +8%) with EBT2. The non-uniformity correction method, after a single film exposure, was applied to the readout of the films. A corrected dose distribution data was subsequently created. The correction method showed more than 10%-better pass ratios in dose difference evaluation than when the correction method was not applied. The red/blue correction method resulted in 5%-improvement compared with the standard procedure that employed red color only. The correction method with EBT2 proved to be able to rapidly correct non-uniformity, and has potential for routine clinical IMRT dose verification if the accuracy of EBT2 is required to be similar to that of EDR2. The use of red/blue correction method may improve the accuracy, but we recommend we should use the red/blue correction method carefully and understand the characteristics of EBT2 for red color only and the red/blue correction method.

Establishment of a flow cytometry screening method for patients with glucose transporter 1 deficiency syndrome.

Objective: We assessed the usefulness of flow cytometry as a functional assay to measure glucose transporter 1 (GLUT1) levels on the surface of red blood cells (RBCs) from Japanese patients with glucose transporter 1 deficiency syndrome (Glut1DS). Methods: We recruited 13 genetically confirmed Glut1DS patients with a solute carrier family 2 member 1 (SLC2A1) mutation (eight missense, one frameshift, two nonsense, and two deletion) and one clinically suspected Glut1DS-like patient without an SLC2A1 mutation, and collected whole blood with informed consent. We stained pelleted RBCs (1 µL) from the patients with a Glut1.RBD ligand and anti-glycophorin A antibody, which recognizes a human RBC membrane protein, and analyzed the cells using flow cytometry. Results: Relative GLUT1 levels quantified by flow cytometry in 11 of 13 patients with definite Glut1DS were 90% below those of healthy controls. Relative GLUT1 levels were not reduced in two of 13 Glut1DS patients who had a missense mutation and no intellectual disability and one Glut1DS-like patient without an SLC2A1 mutation. Relative GLUT1 levels were significantly reduced in Glut1DS patients with an SLC2A1 mutation, more severe intellectual disability, and spasticity. Conclusions: This method to detect GLUT1 levels on RBCs is simple and appears to be an appropriate screening assay to identify severe Glut1DS patients in the early stage before the development of irreversible neurologic damage caused by chronic hypoglycorrhachia.

Evaluation of the four-dimensional motion of lung tumors during end-exhalation breath-hold conditions using volumetric cine computed tomography images.

BACKGROUND AND PURPOSE: This study was performed to evaluate the four-dimensional motion of lung tumors during end-exhalation (EE) breath-holding (BH) using cine computed tomography (CT) and investigate the correlation between tumor and surrogate marker motions. MATERIALS AND METHODS: This study included 28 patients who underwent stereotactic body radiation therapy at our institution and were capable of 15-20 s of EE BH within a ±1.5-mm gating window with external markers. During EE BH with cine CT, 21 s of continuous data were acquired using 320-row multislice CT. Displacements in the tumor position during EE BH were assessed in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions. Pearson's correlation coefficient (r) between tumor motions during EE BH and diaphragm/external marker motions was also determined. RESULTS: The mean absolute maximum displacements of the tumor position during EE BH were 1.3 (range: 0.2-4.0), 1.9 (range: 0.3-12.0), and 1.3 (range: 0.1-7.2) mm in the LR, AP, and SI directions, respectively. The displacement of the tumor position in the AP direction was weakly correlated (|r| < 0.4) with the external marker and diaphragm displacements in many cases (proportions of 50% and 46%, respectively). CONCLUSION: We found some cases showing substantial displacement in lung tumor positions during EE BH, especially in the AP direction. Because these tumor position displacements did not correlate with surrogate markers and were difficult to detect, we recommend pretreatment evaluation of the four-dimensional motions of tumors during BH using cine CT.

Nongenomic effects of fluticasone propionate and budesonide on human airway anion secretion.

This study investigated the physiological effects of inhaled corticosteroids, which are used widely to treat asthma. The application of fluticasone propionate (FP, 100 µM) induced sustained increases in the short-circuit current (I(SC)) in human airway Calu-3 epithelial cells. The FP-induced I(SC) was prevented by the presence of H89 (10 µM, a protein kinase A inhibitor) and SQ22536 (100 µM, an adenylate cyclase inhibitor). The FP-induced responses involved bumetanide (a Na(+)-K(+)-2Cl(-) cotransporter inhibitor)-sensitive and 4,4'-dinitrostilbene-2,2'-disulfonic acid (an inhibitor of HCO(3)(-)-dependent anion transporters)-sensitive components, both of which reflect basolateral anion transport. Further, FP augmented apical membrane Cl(-) current (I(Cl)), reflecting cystic fibrosis transmembrane conductance regulator (CFTR)-mediated conductance, in the nystatin-permeabilized monolayer. In I(SC) and I(Cl) responses, FP failed to enhance the responses to forskolin (10 µM, an adenylate cyclase activator). Nevertheless, we found that FP synergistically increased cytosolic cAMP concentrations in combination with forskolin. All these effects of FP were reproduced with the use of budesonide. Collectively, inhaled corticosteroids such as FP and budesonide stimulate CFTR-mediated anion transport through adenylate cyclase-mediated mechanisms in a nongenomic fashion, thus sharing elements of a common pathway with forskolin. However, the corticosteroids cooperate with forskolin for synergistic cAMP production, suggesting that the corticosteroids and forskolin do not compete with each other to exert their effects on adenylate cyclase. Considering that such synergism was also observed in the FP/salmeterol combination, these nongenomic aspects may play therapeutic roles in mucus congestive airway diseases, in addition to genomic aspects that are generally recognized.