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Introduction. Personal technology devices are now a primary method of note-taking in graduate learning. This study compared student learning outcomes using laptops for digital note-taking compared with handwritten notes. Review of Literature. Various results were reported in the literature of which note-taking method in undergraduate and graduate levels of learning results in best learning outcomes. Subjects. Subjects were 117 first-year doctoral physical therapy students enrolled in a 3-week wound care course. The study was completed over 3 consecutive years. Methods. Subjects volunteered to either use their laptop for digital note-taking or take handwritten notes on slide handouts. After course completion, course grades were compared between the 2 different note-taking method groups. Results. A 1-way analysis of variance yielded no significant difference due to the method of note-taking on overall course grade F (1, 115) =.048 (P =.827). A 2-way analysis of variance yielded no significant interaction between the method of note-taking and gender, but the main effect of gender was significant, with female subjects scoring higher than male subjects. Another 2-way analysis of variance yielded a significant interaction between the method of note-taking and the age of the student F (1, 113) = 9.402 (P =.003), and a simple main effects analysis for age found a significant difference in course grade between the 2 note-taking methods for older students F (1, 113) = 8.923 (P =.003) but not for younger students. This indicates that the effect of note-taking method on the course grade depended on the age group, specifically the older group tended to perform better with handwritten notes. Discussion and Conclusion. With our findings focusing on graduate physical therapy students, we found that handwritten note-takers tended toward having higher course grades, but they did not significantly outperform the digital note-taking group. Our findings found that the age of student and handwritten note-taking resulted in significantly higher course grades. Female gender was also found to be a significant factor for improved classroom performance in this study. Important and Relevance of Work. Results from this study indicated that modality of note-taking may not matter for most students, but it may matter for older students. Older students performed better in the handwritten notes group, and these findings are important to share with course instructors and with older students who may be struggling in graduate coursework. [ABSTRACT FROM AUTHOR]

Background and objective: Isoflurane is commonly used for neurosurgery but the effects of sevoflurane on human cerebral blood flow and cerebral metabolic rate of oxygen have not been fully evaluated. We therefore assessed the effects of sevoflurane and isoflurane on global cerebral blood flow and cerebral metabolic rate of oxygen in patients without noxious stimuli or neurological disorders. Methods: General anaesthesia was induced with midazolam (0.2 mg kg[sup -1]) and fentanyl (5 µg kg[sup -1]) in 20 ASA I patients undergoing knee joint endoscopic surgery. Epidural anaesthesia was also performed to avoid noxious stimuli during surgery. Cerebral blood flow and cerebral arteriovenous oxygen content difference was measured using the Kety-Schmidt method with 15% nitrous oxide as a tracer before and after administration of either sevoflurane or isoflurane (1.5 minimum alveolar concentration, 60 min) and cerebral metabolic rate of oxygen was then calculated. Results: Sevoflurane and isoflurane both increased cerebral blood flow (17%, P < 0.05; 25%, P < 0.05, respectively) and decreased cerebral metabolic rate of oxygen (26%, P < 0.01; 38%, P < 0.01, respectively). There were no significant differences in cerebral blood flow and cerebral metabolic rate of oxygen between sevoflurane and isoflurane. Conclusions: Sevoflurane and isoflurane similarly increased cerebral blood flow and decreased cerebral metabolic rate of oxygen in human beings anaesthetized with midazolam and fentanyl. [ABSTRACT FROM AUTHOR]

Background and objective: When the endotracheal tube cuff is repeatedly aspirated to avoid excessive cuff pressure during nitrous oxide anaesthesia, a stable cuff pressure is eventually achieved. We assessed the time required to achieve a stable cuff pressure after repeated cuff deflation. Methods: During 67% nitrous oxide and oxygen anaesthesia, air-filled cuffs of a standard tracheal tube (Mallinckrodt Hi-Contour®) were repeatedly deflated every 30 min for the first 3 or 4 h to inhibit excessive pressure (Groups Def-3 or Def-4, respectively, n = 10 for each); the cuff pressure was monitored for an additional 3 h. In some patients, the study was terminated at 1, 2, 3 and 4 h (n = 6 for each). Results: Cuff pressure in Group Def-3, but not in Group Def-4, >22 mmHg after stopping cuff aspiration. Intracuff nitrous oxide concentrations increased during repeated cuff deflation and increased further in Group Del-3 during an additional 3 h (from 39.8 ± 4.7% to 44.3 ± 3.8%; P < 0.05), whereas intracuff nitrous oxide concentrations at 4 h were not different from those in Group Def-4 at the end of the study (43.7 ± 4.5% versus 42.3 ± 4.8%; P = 0.579). Conclusions: When the air-filled cuff of the standard endotracheal tube is repeatedly deflated every 30 min for 4 h, but not for only 3 h, during nitrous oxide anaesthesia, a stable cuff pressure can be achieved without further deflation of the cuff. Our data also suggest that achieving an equilibrating nitrous oxide concentration in the cuff provides a subsequent stable cuff pressure. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most common arrhythmia and a major public health burden. Catheter ablation (CA) is an effective treatment of AF. Although radiofrequency catheter ablation (RFCA) is the standard practice, cryoballoon ablation (CBA) has become increasingly popular. Pulmonary dysfunction is also associated with AF. As CA targets the pulmonary vasculature, it poses a risk to lung function. However, the effect of CA on respiration in patients with paroxysmal atrial fibrillation (PAF) post-ablation has not yet been assessed. We assessed pulmonary function after CA in a cohort of patients with AF. This prospective, single-center study included 26 patients with symptomatic PAF and 18 patients without PAF. CA techniques include RFCA, CBA, hot balloon ablation, and laser balloon-mediated ablation. Spirometry parameters included vital capacity (VC), forced vital capacity (FVC), forced expiratory volume (FEV1), and peak expiratory flow, which were all measured 6 months post-ablation. AF ablation significantly improved VC (P = .04), FVC (P = .01), and peak expiratory flow (P = .006) in all the patients. In the patients with PAF, we observed a significant increase in FEV1 (P = .04). CBA significantly improved VC (P = .012) and FVC (P = .013). A significant improvement in these pulmonary parameters was achieved, specifically in patients with PAF treated with an ablation protocol with CBA, but not with RFCA or hot balloon ablation. A significant decrease in FEV1 was observed with hot balloon ablation (P = .035). Significant improvement in pulmonary parameters was observed specifically in patients with PAF who underwent CBA. CBA may be a more suitable treatment strategy for patients with PAF, particularly those with compromised pulmonary function., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: Muscular hemorrhages around the scapula that are caused by upper extremity motion are rarely reported in cases other than drowning. We examined differences in the frequency of muscular hemorrhages around the scapula and stratified them by the cause of death. Muscular hemorrhages were mostly noted in cases of drowning (118/185, 63.8%), followed by cases of asphyxia (23/44, 52.3%). In addition, muscular hemorrhages around the scapula were found in cases of ligature strangulation (8/11, 72.7%), manual strangulation (2/3, 66.7%), choking (11/14, 78.6%), and traumatic asphyxia (2/2, 100%). Muscular hemorrhages were not found in cases of hanging or environmental suffocation, possibly because of the short time interval preceding the loss of consciousness. The distribution of muscular hemorrhages was similar in choking and drowning cases. Muscular hemorrhages due to strangulation were mainly unilateral, whereas those due to choking and drowning were mainly bilateral. During all types of asphyxia, muscular hemorrhages around the scapula were considered to be the result of conscious, active upper extremity motion. Because the frequency and laterality of muscular hemorrhages around the scapula differed based on the type of asphyxia, our findings provide insights into the manner of asphyxia that could be used to aid in the identification of homicidal hangings., Competing Interests: The authors report no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: In principle, reconstruction in macrostomia requires symmetry and accurate positioning of the newly reconstructed commissure. The proper position of the new commissure can be determined by several methods. In the determination of the new commissure of bilateral cases, generally the average length of the lips or the distance from anatomical landmarks other than the lips, such as the pupils or tragi, has been used. A new approach was reported by Tse et al in 2018: the anatomic approximation approach. Macrostomia repair refers to anatomical landmarks in the lips to determine the new commissure. The authors performed surgery using this anatomic approximation approach for bilateral macrostomia and achieved the good results., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by Mutaz B. Habal, MD.)

Objectives: In patients with severe acute pancreatitis (SAP), early enteral nutrition (EN) is recommended by major clinical practice guidelines, but the exact timing for the initiation of EN is unknown., Methods: We conducted a post hoc analysis of the database for a multicenter (44 institutions) retrospective study of patients with SAP in Japan. The patients were classified into 3 groups according to the timing of EN initiation after the diagnosis of SAP: within 24 hours, between 24 and 48 hours, and more than 48 hours. The primary outcome was in-hospital mortality., Results: Of the 1094 study patients, 176, 120, and 798 patients started EN within 24 hours, between 24 and 48 hours, and more than 48 hours after SAP diagnosis, respectively. On multivariable analysis, hospital mortality was significantly better with EN within 48 hours than with more than 48 hours (adjusted odds ratio, 0.49; 95% confidence interval, 0.29-0.83; P < 0.001) but did not significantly differ between the groups with EN starting within 24 hours and between 24 and 48 hours (P = 0.29)., Conclusions: Enteral nutrition within 24 hours may not confer any additional benefit on clinical outcomes compared with EN between 24 and 48 hours., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Postmortem computed tomography (PMCT) is used commonly in forensic medicine. Postmortem computed tomography of the head provides information on the eyes and orbits and may reveal intraocular abnormalities. We present a case in which the identity of a deceased man was confirmed by the presence of aphakic eyes detected on PMCT. A decomposed body was found in a house and suspected to be a man in his 40s who lived alone. Autopsy identified pontine hemorrhage as the cause of death. Although signs of previous dental treatment were evident, the storage period of the householder's dental records had expired. He had no family members to provide DNA for a comparative DNA analysis. Postmortem computed tomography before autopsy revealed aphakia (ie, the absence of eye lenses) suggestive of previous ocular surgery. His medical records revealed that he had undergone ocular surgery for secondary glaucoma due to uveitis, which had resulted in artificial aphakia. Peripheral iridectomy scars fully matched the findings in his medical records, thus identifying the body. The unusual finding of artificial aphakia in a man in his 40s facilitated the personal identification in this case. In conclusion, PMCT provides additional information, and the correct interpretation of intraocular PMCT findings by forensic pathologists is crucial.

Objective: Antimicrobial prophylaxis is not generally recommended for patients with severe acute pancreatitis (SAP) owing to the limited clinical benefits. Nonetheless, it is frequently administered in actual practice given the patients' critical condition and the lack of solid evidence showing adverse effects of antimicrobial prophylaxis. We evaluated herein an association between antimicrobial prophylaxis and invasive pancreatic candidiasis as an adverse effect in patients with SAP., Methods: This is a retrospective cohort study of all consecutive patients with SAP who were admitted to the study institutions (n = 44) between January 1, 2009, and December 31, 2013. We performed multivariable logistic regression analysis adjusting for the extent of pancreatic necrosis and surgical interventions for invasive pancreatic candidiasis., Results: Of the 1097 patients with SAP, 850 (77.5%) received antimicrobial prophylaxis, and 21 (1.9%) had invasive pancreatic candidiasis. In multivariable logistic regression analysis, antimicrobial prophylaxis was significantly associated with the development of invasive pancreatic candidiasis (adjusted odds ratio, 4.23; 95% confidence interval, 1.14-27.6) (P = 0.029)., Conclusions: The results suggest that antimicrobial prophylaxis may contribute to the development of invasive pancreatic candidiasis, and therefore, the routine use of antimicrobial prophylaxis for SAP may be discouraged.

Purpose of Review: Optimal nutritional therapy has been associated with better clinical outcomes and requires providing energy as closed as possible to measured energy expenditure. We reviewed the current innovations in energy expenditure assessment in humans, focusing on indirect calorimetry and other new alternative methods., Recent Findings: Although considered the reference method to measure energy expenditure, the use of indirect calorimetry is currently limited by the lack of an adequate device. However, recent technical developments may allow a broader use of indirect calorimetry for in-patients and out-patients. An ongoing international academic initiative to develop a new indirect calorimeter aimed to provide innovative and affordable technical solutions for many of the current limitations of indirect calorimetry. New alternative methods to indirect calorimetry, including CO2 measurements in mechanically ventilated patients, isotopic approaches and accelerometry-based fitness equipments, show promises but have been either poorly studied and/or are not accurate compared to indirect calorimetry. Therefore, to date, energy expenditure measured by indirect calorimetry remains the gold standard to guide nutritional therapy., Summary: Some new innovative methods are demonstrating promises in energy expenditure assessment, but still need to be validated. There is an ongoing need for easy-to-use, accurate and affordable indirect calorimeter for daily use in in-patients and out-patients.

The increase in incidence of colonic diverticular bleeding is relative to an age-related rise in the incidence of colonic diverticulosis and use of antithrombotic medication. However, risk factors related to the onset, recurrence, and prophylaxis have not been established. Therefore, we aimed to determine risk factors for the onset and recurrence of colonic diverticular bleeding.An age- and sex-matched case-control study was performed to assess the risk factors for the onset of colonic diverticular bleeding. The distribution of diverticulosis, comorbidity, and medication were evaluated from medical records. We also assigned patients with a first-time bleeding into groups with and without rebleeding during follow-up to determine risk factors for recurrence.Bilateral colonic diverticulosis, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin (LDA), and anticoagulants were significant risk factors for the onset of colonic diverticular bleeding on multivariate analysis. In contrast, the use of selective cyclooxygenase-2 (COX-2) inhibitor was not a risk factor for the onset. The incidence of bleeding in direct oral anticoagulant and warfarin users was not different between the 2 groups. The cumulative recurrence rate at 1 year was 15%. Recurrence rate was significantly higher in patients with a prior history of colonic diverticular bleeding than those without. Steroid use was associated with recurrence.Extensive distribution of diverticulosis and use of nonselective NSAIDs, LDA, and anticoagulants are regarded as risk factors for the onset of colonic diverticular bleeding. In addition, a prior history of colonic diverticular bleeding is related to the recurrence.

Objectives: To describe three patients of patulous Eustachian tube (pET) after trigeminal nerve injury and to demonstrate for the first time their magnetic resonance imaging (MRI) findings to hypothesize the mechanism of the pET after trigeminal nerve injury., Patients: Three patients presented with autophony after trigeminal nerve injury caused by the removal of intracranial tumors., Main Outcome Measures: Clinical patient records, audiological data, and MRI., Results: Each patient initially developed transient otitis media with effusion (OME) within a few months after surgery and subsequently developed pET. The MRI of the three patients when they developed pET demonstrated atrophy and fat infiltration of the muscles innervated by the mandibular branch of the trigeminal nerve., Conclusion: All three patients transiently manifested OME before pET was diagnosed. Based on the MRI findings and anatomical considerations, this chronological transition from OME to pET was speculated as an initial motor paralysis of the tensor veli palatini muscle, followed by volume decrease of the muscles in the vicinity of the ET due to denervation atrophy and fat infiltration, which resulted in ET closing failure.

Objective: The aim of this study was to investigate the outcomes of severe acute pancreatitis (SAP) according to the segment presenting with low enhanced pancreatic parenchyma (LEPP) on early contrast-enhanced computed tomography., Methods: This was a post hoc analysis of a multicenter, retrospective study conducted at 44 institutions in Japan. Patients diagnosed as having SAP according to the Japanese Severity Score between January 2009 and December 2013 were included. We compared the effect of LEPP in each segment on mortality., Results: A total of 1097 patients were assessed. The numbers of patients with LEPP in the pancreatic head (Ph), body (Pb), or tail (Pt) were 272, 273, and 204 (with some overlaps), respectively. In multivariate analysis, LEPP in Ph and Pt was significantly related to mortality (odds ratio [OR], 1.94; 95% confidence interval [CI], 1.11-3.40 [P < 0.05], for LEPP in Ph; OR, 2.44; 95% CI, 1.27-4.67 [P < 0.05], for LEPP in Pt), but LEPP in Pb was unrelated to mortality (OR, 0.70; 95% CI, 0.35-1.37; P = 0.30)., Conclusions: Presence of LEPP in Ph and Pt on early contrast-enhanced computed tomography was independently associated with increased mortality in SAP. These patients require close observation to ensure timely and adequate intervention.

Objective: The aim of this study is to assess the effectiveness of continuous regional arterial infusion (CRAI) of protease inhibitors in patients with severe acute pancreatitis (SAP) including acute necrotizing pancreatitis., Methods: This retrospective study was conducted among 44 institutions in Japan from 2009 to 2013. Patients 18 years or older diagnosed with SAP according to the criteria of the Japanese Ministry of Health, Labour and Welfare study group (2008) were consecutively enrolled. We evaluated the association between CRAI of protease inhibitors and mortality, incidence of infection, and the need for surgical intervention using multivariable logistic regression analysis., Results: Of 1159 patients admitted, 1097 patients with all required data were included for analysis. Three hundred and seventy-four (34.1%) patients underwent CRAI of protease inhibitors and 723 (65.9%) did not. In multivariable analysis, CRAI of protease inhibitors was not associated with a reduction in mortality, infection rate, or need for surgical intervention (odds ratio [OR] 0.79, 95% confidence interval [CI] 0.47-1.32, P = 0.36; OR 0.97, 95% CI 0.61-1.54, P = 0.89; OR 0.76, 95% CI 0.50-1.15, P = 0.19; respectively)., Conclusions: Continuous regional arterial infusion of protease inhibitors was not efficacious in the treatment of patients with SAP.

Purpose of Review: The review focuses on the use of parenteral nutrition and enteral nutrition in critically ill patients to optimize the nutrition care throughout the ICU stay. The key message is: you have the choice!, Recent Findings: Enteral nutrition has been recommended for critically ill patients, whereas parenteral nutrition has been considered harmful and to be avoided. However, recent studies have challenged this theory. They demonstrated that enteral nutrition is frequently associated with energy and protein undernutrition, whereas parenteral nutrition becomes deleterious only if overfeeding is induced. Measuring energy expenditure by indirect calorimetry, in most cases, enables accurate determination of the energy needs to optimize the prescription of nutrition. Protein targets should also be considered for adequate feeding. Parenteral nutrition can be used as a supplement or as an alternative to enteral nutrition in case of gastrointestinal intolerance, to enable adequate energy, and protein provision., Summary: Parenteral nutrition is a powerful tool to optimize nutrition care of critically ill patients to improve clinical outcome, if prescribed according to the individual needs of the patients. After 3-4 days of attempt to feed enterally, enteral nutrition or parenteral nutrition can be used alternatively or combined, as long as the target is reached with special attention to avoid hypercaloric feeding.

Purpose of Review: Patients who continue to experience heartburn symptoms despite adequate-dose proton pump inhibitor therapy have unmet clinical needs. In this review, we focus on the most recent findings related to the mechanism of heartburn symptom generation, and on the treatment of gastroesophageal reflux disease-related and functional heartburn., Recent Findings: The immunological mechanism in the esophageal mucosa has been addressed as a potential mechanism of the onset of esophageal mucosa damage and the generation of heartburn symptoms. Peripheral or central hypersensitivity in viscera is a potentially unifying pathophysiological concept in functional heartburn. Vonoprazan, a novel and potent first-in-class potassium-competitive acid blocker, is expected to prove useful in the treatment of reflux disease., Summary: New findings in the mechanisms of heartburn symptom generation are emerging, including the immunological mediation of esophageal mucosal damage and the development of visceral hypersensitivity in functional heartburn. In the future, we anticipate the emergence of new and specific therapeutic options based on these mechanisms, with less dependence on acid-suppressing agents.

Purpose of Review: The difficulties to feed the patients adequately with enteral nutrition alone have drawn the attention of the clinicians toward the use of parenteral nutrition, although recommendations by the recent guidelines are conflicting. This review focuses on the intrinsic role of parenteral nutrition, its new indication, and modalities of use for the critically ill patients., Recent Findings: A recent trial demonstrated that selecting either parenteral nutrition or enteral nutrition for early nutrition has no impact on clinical outcomes. However, it must be acknowledged that the risk of relative overfeeding is greater when using parenteral nutrition and the risk of underfeeding is greater when using enteral nutrition because of gastrointestinal intolerance. Both overfeeding and underfeeding in the critically ill patients are associated with deleterious outcomes. Thus, early and adequate feeding according to the specific energy needs can be recommended as the optimal feeding strategy., Summary: Parenteral nutrition can be used to substitute or supplement enteral nutrition, if adequately prescribed. Testing for enteral nutrition tolerance during 2-3 days after ICU admission provides the perfect timing to start parenteral nutrition, if needed. In case of absolute contraindication for enteral nutrition, consider starting parenteral nutrition carefully to avoid overfeeding.

Objective: Preservation of residual hearing during cochlear implantation is important. This study investigated changes in endocochlear potential (EP) during simulated cochlear implant (CI) electrode insertion., Study Design: Laboratory animal study., Setting: Academic hospital laboratory., Subjects and Methods: Guinea pigs were divided into 4 groups: cochleostomy only (4 animals), suction after cochleostomy (5 animals), simulated CI electrode insertion parallel to the longitudinal axis of the scala tympani without suctioning (7 animals), and simulated CI electrode insertion toward the modiolus without suctioning (7 animals). The EP was measured from the second turn of the cochlea, and the values after 20 minutes were compared., Results: The EP showed little change at 20 minutes after cochleostomy with a nearly normal value of 84.83 ± 2.12 mV. Suctioning of the perilymph from the cochleostomy site caused a slight acute reduction in EP by about 6 mV, and the value at 20 minutes after cochleostomy was 78.64 ± 4.42 mV. Insertion of the simulated CI electrode parallel to the longitudinal axis of the scala tympani caused a slight decrease in EP to 78.91 ± 5.06 mV. Insertion toward the modiolus caused a marked decrease in EP to 54.13 ± 4.42 mV at 20 minutes after the treatment, significantly lower compared with the other 3 groups., Conclusion: EP was well preserved during carefully performed surgical procedures of simulated CI electrode insertion, but it decreased significantly if the simulated CI electrode was inserted toward the modiolus. Careful attention is necessary to ensure the correct direction of CI electrode insertion to preserve residual hearing. Use of suction should be minimized if possible.

Perturbation of cochlear microcirculation, that is, ischemia is a major cause of hearing impairment. Earlier studies examined the short-term (≤7 days) effect of cochlear ischemia. This study characterized the long-term (4 weeks) functional and morphological changes in adult guinea pig cochleae subject to transient ischemia by clamping the labyrinthine artery for 0.25-3 h. Notably, cochlear ischemia for over 1 h caused an increase of auditory brainstem response thresholds and loss of high-frequency hearing, basal-turn hair cells, and spiral ganglions. Auditory recovery may be possible after 30-min ischemia. The extent of the functional and morphological changes depended on the ischemia period, and the changes progressed in extent from the apical to the basal turn in an orderly fashion.

The endolymphatic calcium concentration [Ca2+] is essential for acoustic transduction. This study investigated the changes in cochlear function caused by vestibular labyrinth destruction in the acute phase by measurement of the endocochlear potential and endolymphatic [Ca2+].Hartley guinea pigs underwent lateral semicircular canal transection with suctioning of the perilymph, ampullectomy, or destruction of the lateral part of the vestibule. The endocochlear potential and endolymphatic [Ca2+] showed mild change after lateral semicircular canal transection with suctioning or ampullectomy. However, the endocochlear potential decreased drastically and permanently, and the endolymphatic [Ca2+] elevated suddenly but finally normalized after vestibulotomy. Elevated endolymphatic [Ca2+] is important in the disturbance of the mechanism of cochlear function caused by vestibular labyrinth destruction.

Previously, we synthesized a series of hydrazide class of compounds and examined their cytotoxicity in a number of cancer cell lines. Among these analogues, SC144 exhibited potent cytotoxicity against a panel of drug-sensitive and drug-resistant cancer cell lines. To further explore its therapeutic potentials in the combination settings, we evaluated the synergy between SC144 and selected conventional chemotherapeutic agents in in-vitro cancer cell models. SC144 showed synergism with both 5-fluorouracil and oxaliplatin when cotreated in colorectal cancer HT29 cells. Pretreatment with SC144 in oxaliplatin-resistant HTOXAR3 cells was more effective than oxaliplatin pretreatment. In addition, the combination of SC144 and paclitaxel exhibited synergism in MDA-MB-435 cells with a schedule-dependent block in cell cycle. In an MDA-MB-435 mouse xenograft model, coadministration of SC144 and paclitaxel delayed tumor growth in an SC144 dose-dependent manner. Evaluation of the pharmacokinetics of SC144 revealed that intraperitoneal administration of SC144 showed a two-compartmental pharmacokinetics elimination profile that was not observed in the oral dosing. In summary, these studies further validate SC144 as a novel anticancer agent and provide insights for developing combination therapies for both drug-sensitive and drug-resistant cancers.

Objective: Computed tomography (CT) in the sitting position was useful for detecting patulous Eustachian tube (ET)., Study Design: Retrospective., Setting: Tertiary referral center., Patients: Eighty-seven patients divided into two groups. The patulous ET group consisted of 111 ears of 67 patients with patulous ET. The control group consisted of 30 ears of 20 patients without symptoms characteristic of patulous ET or abnormal findings in ET function tests., Main Outcome Measures: CT was performed under the resting condition and during Valsalva maneuver (Valsalva condition). The multiplanar reconstruction technique was used to reconstruct 1-mm-thick gapless images parallel to and perpendicular to the ET long axis. The open tubal distance (OTD) and average ET-gram were examined., Results: The OTD was significantly longer in the patulous ET group than in the control group under both resting and Valsalva conditions (both p < 0.001). The OTD was also significantly longer under the Valsalva condition than under the resting condition in both groups (p < 0.01 in the patulous ET group, p < 0.001 in the control group). The average ET-gram showed an occlusive zone in the cartilaginous portion medial to the isthmus under both the resting and Valsalva conditions in the control group (n = 30). However, the occlusive zone could not be observed under either the resting or Valsalva conditions in the patulous ET group (n = 111). Completely patent (open) ET was observed with continuous hyperlucency from the pharyngeal to the tympanic orifices in 88 of 111 patients in the patulous ET group, but in none of the control group, indicative of 100% specificity., Conclusion: Computed tomography in the sitting position employing Valsalva maneuver is useful for the diagnosis of patulous ET.

Objective: Nasal-noise masking audiometry was developed to assess the acoustic transfer function from the nasopharyngeal cavity to the middle ear via patulous eustachian tube (ET)., Study Design: Prospective., Setting: Tertiary referral center., Patients: Twenty-seven ears of 18 patients with patulous ET and 20 ears of 10 healthy subjects with no history of ear disease or complaints of aural symptoms., Main Outcome Measures: Audiometric measurement was conducted with and without masking noise presented in the nasal cavity., Results: The masking effect of nasally presented noise caused elevation of the threshold for the tone presented in the external auditory canal. This threshold elevation was significantly greater, particularly in the lower-frequency region, in ears with patulous ET and was decreased to the normal range after obstructive treatment of the patulous ET., Conclusion: Nasal-noise masking audiometry is a simple and effective way to identify patulous ET.

Objective: Smoking is associated with endothelial dysfunction and activated Rho-kinase in vascular smooth muscle cells (VSMCs) in humans. The purpose of this study was to elucidate the relationship between endothelial function and Rho-kinase activity in forearm VSMCs in healthy young men., Methods and Results: We evaluated the forearm blood flow (FBF) responses to acetylcholine (ACh), fasudil, a Rho-kinase inhibitor, and sodium nitroprusside (SNP) in male smokers (n=10) and nonsmokers (n=14). FBF was measured by using a strain-gauge plethysmography. The vasodilatory effect of ACh was significantly smaller in smokers than that in nonsmokers. The vasodilatory effect of fasudil was significantly greater in smokers than that in nonsmokers. The vasodilatory effects of SNP in the 2 groups were similar. There was a significant correlation between the maximal FBF response to fasudil and that to ACh (r=-0.67; P<0.01). There was no significant correlation between the maximal FBF response to fasudil and that to SNP. The intra-arterial coinfusion of fasudil significantly increased the FBF response to ACh in smokers but not in nonsmokers. There were no significant differences between FBF response to fasudil alone and that in combination with NG-monomethyl-L-arginine in smokers and in nonsmokers. The intra-arterial coinfusion ascorbic acid did not alter the FBF response to fasudil in both groups., Conclusions: These findings suggest that smoking is involved in not only endothelial dysfunction but also activation of Rho-kinase in VSMCs in forearm circulation, and that there is a significant correlation between endothelial function and Rho-kinase activity in VSMCs.

Purpose: Although normal cornea is an avascular transparent structure, bone marrow (BM)-derived cells exist in situ even in noninflamed conditions. We evaluated constitutive cellular trafficking into the cornea in the naive state and investigated how corneal inflammation may be initiated by various stimuli., Methods: BM chimeric mice were generated using BM from enhanced green fluorescent protein (eGFP) transgenic mice. Corneas of chimeric mice were carefully studied by fluorescent biomicroscopy until 6 months after transplantation. To analyze initiation of cellular events in corneal immune response, we cauterized the center of the cornea or inoculated IL-1 beta into the corneal micropocket. Cellular events were analyzed by flow cytometry., Results: At 2 weeks after BM transplantation, GFP cells gradually migrated into the cornea from the limbal area and were distributed over the entire cornea at 6 months. In both the cauterization and micropocket assays, infiltration of neutrophils and macrophages occurred on days 2 and 4, respectively. Depletion of neutrophils by anti-Gr-1 Ab significantly reduced corneal edema/opacity induced by cauterization. IL-1 beta-induced angiogenesis was markedly reduced in monocyte chemoattractant protein-1 knockout mice., Conclusions: BM-derived cells are recruited into the normal cornea and may be essential to maintain corneal clarity. In the inflamed cornea, neutrophils might be responsible for acute corneal edema/opacity and macrophages for corneal angiogenesis and chronic inflammation.

Experimental studies have shown that adrenomedullin (AM) causes vasodilation, in part, mediated by endothelium-derived nitric oxide (NO). However, it remains to be clarified how NO is involved in AM-induced coronary vasoreactivity in humans. We examined whether NO contributes to the vasodilatory effects of adrenomedullin on human coronary arteries. In 10 patients with angiographically normal coronary arteries, adrenomedullin (low dose: 1 ng/kg/min; high dose: 10 ng/kg/min) was infused into the left coronary ostium before and after an infusion of N-monomethyl-L-arginine (L-NMMA, 40 micromol/min for 5 min), an NO synthase inhibitor. Coronary diameter and coronary blood flow (CBF) were evaluated by quantitative angiography and Doppler flow velocity measurements. Changes in these parameters in response to adrenomedullin were expressed as percent changes from baseline values. Adrenomedullin at a high dose dilated coronary arteries (3.7+/-0.5%, P<0.001). Adrenomedullin increased the coronary blood flow at both doses (low: 55.7+/-13.9%, P<0.01; high: 48.8+/-9.8%, P<0.001). After the infusion of L-NMMA, adrenomedullin-induced coronary vasodilation and increase in coronary blood flow were attenuated. These findings suggest that adrenomedullin dilates human coronary arteries through an increase in NO production, at least in part.

Unlabelled: Although yawning occurs frequently during the IV induction of general anesthesia, the significance of this response remains unknown. In this study, we induced 30 surgical patients with 4 mg/kg thiopental IV, and 30 patients with 2 mg/kg propofol IV. Thereafter, the occurrence of yawning was continuously assessed, as the only clinical end-point, for 1 min. The electroencephalographic bispectral index was monitored throughout the observation period. The criterion for an arousal response was a transient increase during a continuing decrease in the bispectral index value. On the basis of this criterion, the sensitivity and specificity of the yawning response as an arousal sign were 77% and 80%, respectively. If a patient exhibited a yawning response, the chance of arousal was 84% (positive predictive value). With no yawning response, the chance of nonarousal was 71% (negative predictive value). According to simple logistic regression, the yawning response was predictive of a transient arousal-shift with an odds ratio of 13.5 (95% confidence interval: 3.8-48; P < 0.001). The occurrence of a yawning response during IV induction may be a clinical indicator of a transient arousal-shift during progressive loss of consciousness., Implications: Yawning elicited by IV anesthetic induction was related to a transient increase during the continuing decrease in the electroencephalographic bispectral index value (sensitivity and specificity, 77% and 80%, respectively). This type of yawning may be a clinical indicator of a transient arousal-shift during progressive loss of consciousness.

Nicorandil, N-(2-hydroxyethyl)-nicotinamide nitrate, exerts its vasodilatory effects by opening ATP-sensitive potassium (K-ATP) channels and by acting as the exogenous nitric oxide (NO). It is not clear, however, whether the actions of other endothelium-dependent vasodilators, such as NO, endothelium-derived hyperpolarizing factor (EDHF), and prostaglandins, contribute to nicorandil-induced vasodilation in the vasculature in humans. We evaluated forearm blood flow (FBF) response to intraarterial infusion of nicorandil alone and in the presence of glibenclamide, a K-ATP channel inhibitor, N(G)-monomethyl-L-arginine, an NO synthase inhibitor, indomethacin, a cyclooxygenase inhibitor, or miconazol, a cytochrome P-450 inhibitor, in 24 healthy male subjects. FBF was measured using strain-gauge plethysmography. Infusion of nicorandil significantly increased the FBF response in a dose-dependent manner. Intraarterial infusion of glibenclamide attenuated nicorandil-induced vasodilation (160.9 +/- 21.2% versus 90.2 +/- 19.4%, P < 0.01), and miconazole also attenuated the FBF response to nicorandil (160.9 +/- 21.2% versus 66.1 +/- 9.2%, P < 0.001). N-monomethyl-L-arginine or indomethacin did not alter the FBF response to nicorandil. These findings suggest that nicorandil causes vasodilation in forearm circulation in humans, at least in part through a pathway that is dependent on K-ATP channels and cytochrome P-450, but not on endogenous NO and prostaglandins. EDHF may contribute to nicorandil-induced vasodilation in humans.

Objectives: It is often difficult to differentiate benign from malignant intraductal papillary mucinous tumors (IPMTs). This study aimed to differentiate them using various imaging techniques., Methods: Receiver operating characteristic curves were used to establish optimal cutoff values to differentiate benign from malignant tumors in 121 patients with histologically confirmed IPMTs., Results: For branch duct type, accuracy for malignancy was highest using endoscopic ultrasonography (EUS) to measure the cyst diameter, and accuracy was 68.2% at a cutoff value of 33.9 mm. For main duct type, accuracy was highest, 71.1% at a cutoff value of 8.4 mm for main duct diameter, with magnetic resonance cholangiopancreatography. For all imaging techniques and findings, accuracy was highest using EUS, 76.4% at a cutoff value of 5.4 mm for height of protrusion. Each imaging technique had a positive predictive value of 80% if the cut off value for the height of the protruding lesion was met., Conclusions: Malignancy can be strongly suspected when the height of protrusion exceeds the respective cutoff values. EUS was most effective to differentiate benign IPMTs from malignant tumors by assessing the height of protrusion.

Unlabelled: The mechanism by which volatile anesthetics exert inconsistent effects on hiccups is unknown. We elicited a hiccup-like reflex by mechanical stimulation of the dorsal epipharynx in mechanically ventilated cats. The magnitude of the hiccup-like reflex was measured as the peak negative esophageal pressure (nPes) generated against an occluded airway. First, we examined the effects of different end-expiratory concentrations of isoflurane on nPes. Second, we determined the effects of 1.0 minimum alveolar anesthetic concentration of isoflurane on nPes after a peripherally restricted gamma aminobutyric acid (GABA)(A)-receptor antagonist, bicuculline methiodide (BM), a GABA(B)-receptor antagonist, CGP 35348, a peripherally restricted GABA(B)-receptor antagonist, CGP 54626, or saline had been administered IV. Third, BM, CGP 35348, or artificial cerebrospinal fluid was administered intracisternally before 1.0 minimum alveolar anesthetic concentration of isoflurane exposure. During isoflurane anesthesia, nPes was inversely proportional to the end-expiratory isoflurane concentration. The rank order of nPes values obtained after IV drug pretreatment and isoflurane exposure was BM < saline < CGP54626 < CGP35348. After intracisternal drug pretreatment and isoflurane administration, the order of nPes was BM < artificial cerebrospinal fluid < CGP35348. Isoflurane modulates the hiccup-like reflex in opposite directions through both central and peripheral GABA(A) and GABA(B) receptors, with the net effect being a dose-dependent suppression., Implications: Isoflurane facilitated the hiccup-like reflex through activation of central and peripheral gamma aminobutyric acid (GABA)(A) receptors but suppressed it via activation of central and peripheral GABA(B) receptors. The net result was that the hiccup-like reflex was inhibited in proportion to the alveolar isoflurane concentration.

Angiotensin II (Ang II) stimulates protein synthesis in vascular smooth muscle cells (VSMCs), possibly secondary to regulatory changes at the initiation of mRNA translation. Mitogen-activated protein (MAP) kinase signal-integrating kinase-1 (Mnk1), a substrate of ERK and p38 MAP kinase, phosphorylates eukaryotic initiation factor 4E (eIF4E), an important factor in translation. The goal of the present study was to investigate the role of Mnk1 in Ang II-induced protein synthesis and to characterize the molecular mechanisms by which Mnk1 and eIF4E is activated in rat VSMCs. Ang II treatment resulted in increased Mnk1 activity and eIF4E phosphorylation. Expression of a dominant-negative Mnk1 mutant abolished Ang II-induced eIF4E phosphorylation. PD98059 or introduction of kinase-inactive MEK1/MKK1, but not SB202190 or kinase-inactive p38 MAP kinase, inhibited Ang II-induced Mnk1 activation and eIF4E phosphorylation, suggesting that ERK, but not p38 MAP kinase, is required for Ang II-induced Mnk1-eIF4E activation. Further, dominant-negative constructs for Ras, but not for Rho, Rac, or Cdc42, abolished Ang II-induced Mnk1 activation. Finally, treatment of VSMCs with CGP57380, a novel specific kinase inhibitor of Mnk1, resulted in dose-dependent decreases in Ang II-stimulated phosphorylation of eIF4E, protein synthesis, and VSMC hypertrophy. In summary, these data demonstrated that (1) Ang II-induced Mnk1 activation is mediated by the Ras-ERK cascade in VSMCs, and (2) Mnk1 is involved in Ang II-mediated protein synthesis and hypertrophy, presumably through the activation of translation-initiation. The Mnk1-eIF4E pathway may provide new insights into molecular mechanisms involved in vascular hypertrophy and other Ang II-mediated pathological states.