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Objectives: Disruptive clinician behavior worsens communication, information transfer, and teamwork, all of which negatively affect patient safety. Improving safety in medical care requires an accurate assessment of the damage caused by disruptive clinician behavior. Psychometric scales complement case reports, but existing scales have significant limitations. Therefore, this study developed a psychometric scale based on the psychological paradigm to assess disruptive clinician behavior., Methods: The scale was developed through a sequence of steps. First, we used an open-ended questionnaire targeting 712 nurses, content analysis, and content validity assessment by 5 experts to determine valid items for disruptive clinical behavior. Next, an Internet questionnaire survey targeting 1000 health care staff, exploratory factor analysis, and subfactor analysis was conducted to identify necessary and sufficient factors. Then, we calculated difficulty level and discriminative power. We also conducted a field questionnaire survey targeting 84 staff in a hospital. Finally, we calculated ω coefficients and then used confirmatory factor analysis to verify the fit of the hypothesized model., Results: Our open-ended survey involving 478 nurses identified 47 codes in 9 categories. The questionnaire survey involving hospital 1000 medical staff identified 6 factors, with 1 factor subdivided into 4 subfactors and 1 into 2 subfactors. The goodness of fit of the hypothesized 10-factor models with factor pairs and groups was confirmed., Conclusions: We developed a psychometric scale measuring subjective assessments of harm covering various disruptive clinician behaviors. The scale complements interviews and case reports by generating valid, reliable scores for various disruptive clinician behaviors in health care institutions., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: Problematic Internet use (PIU) is common and likely to coexist with mental health problems among adolescents with school refusal behavior. To date, no study has revealed to what extent PIU relates to the daily burden compared with other mental health problems. This study has examined the association between daily difficulties and PIU among adolescents with school refusal behaviors.This cross-sectional study involved all first-visit patients, regardless of diagnosis, aged 10 to 18 years at 2 child/adolescent psychiatric outpatient clinics in Yokohama City, Japan, from April 2016 to March 2018. The Questionnaire-Children with Difficulties (QCD) were obtained from parents. Simultaneously, the severity of PIU was evaluated using the Internet Addiction Test and depressive and anxiety symptoms were evaluated using the Patient Health Questionnaire-9 and General Anxiety Disorder-7 scale in the 2 weeks before the first-visit. From 684 first-visit patients, 227 with school refusal behaviors were enrolled in the study.PIU was observed in 40% of adolescents with school refusal behaviors. The QCD scores among patients with PIU were significantly lower than those in patients without PIU. Linear regression analysis revealed relationships between PIU and lower QCD scores throughout the day (except at night) and the total score of the day, after controlling for confounders such as depressive and anxiety symptoms.In conclusion, among adolescents with school refusal behaviors, PIU may affect their parent-assessed daily difficulties particularly experienced throughout the day., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

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.)

Vascular lesions, including hemangiomas and vascular malformations, are common benign diseases. More than 50% originate from blood vessels or vascular structures and are locate in the head and neck region. This study aimed to evaluate the efficiency and safety of a combination of laser treatments for oral venous malformations using ultrasound navigation. This study reports 3 cases of massive vascular malformation in the oral cavity, which were treated by a combination of a multiple spotted transmucosal irradiation technique (the so-called leopard technique) for the superficial layer, and intralesional photocoagulation for the deep layer using a neodymium-doped yttrium aluminum garnet laser, under real-time ultrasound navigation. All cases presented with a venous malformation with multiple blue swellings on the dorsum of the tongue, which had a maximum dimension of over 30 mm. The percent reduction in the size of the lesions was determined by magnetic resonance imaging. All cases showed a decrease in lesion volume of over 80%, without extensive tissue necrosis, 6 to 12 months after the laser treatment. None of the patients experienced any complications, and all were satisfied with the treatment outcome after one irradiation session.The results of this study suggest that laser treatment using ultrasound navigation is a promising approach for the safe and minimally invasive resolution of oral vascular lesions without scarring and loss of normal tissue architecture, sensation, oral function.

A surgical approach to zygomaticomaxillary complex (ZMC) fracture has not been standardized. The authors reviewed 15 cases of ZMC fractures treated with the swinging eyelid approach and evaluated the effectiveness of the technique by an observational study of Japanese patients. Results were assessed from authentic and functional perspectives: the presence of entropion/ectropion, external canthal malposition and chemosis of the conjunctiva. After a minimum follow-up of 10 months, no patients had lower eyelid ectropion, entropion or retraction. Wounds appeared inconspicuous, and a lateral canthal shape was preserved. No post-operative chemosis of the conjunctiva was observed. Each case was evaluated based on patient satisfaction about their aesthetic outcomes. Patient self-assessment is classified into 4 groups (excellent, good, fair, and unsatisfactory). Thirteen patients were assessed to have an "excellent" outcome, and 2 patients were assessed to have a "good" outcome. No patients had "fair" or "unsatisfactory" outcomes. Avoidance of scarring is a goal of every craniofacial surgeon. The swinging eyelid approach to ZMC fractures offers a simple alternative to the conventional technique. It is versatile and provides sufficient exposure to surgical fields with less visible scar because skin incision is made along the natural crease line, "the crow's feet."

Objective: To report hearing preservation results after retrolabyrinthine vestibular schwannoma surgery, using a new system for continuous near real-time monitoring of cochlear nerve function., Study Design: Retrospective chart review., Setting: Tertiary referral center, University Hospital., Patients: Thirty-one consecutive patients with growing vestibular schwannomas and opting for hearing preservation surgery., Interventions: Tumor removal by a modified, extended retrolabyrinthine approach, using a new system for continuous near real-time monitoring of cochlear nerve function., Main Outcome Measures: Pure-tone average and speech discrimination (SD) 1-year postoperative. Preservation of word recognition score class. Preservation of serviceable hearing (SD>50%)., Results: Any hearing was preserved in 83 and 69% had preserved word recognition score class or better. Serviceable hearing was preserved in 77%. SD was unchanged in 48%, improved in 21%, and poorer in 31%. Of 18 patients with potential for improvement (SD 90% or worse preoperatively), 33% improved (SD increase 10% or more)., Conclusion: The hearing preservation rate is favorable using the modified, extended retrolabyrinthine approach and a new system for continuous near real-time monitoring of cochlear nerve function for removal of growing vestibular schwannomas, as 77% preserved serviceable hearing 1 year after surgery. Hearing improved after surgery in 33%. Using the new neuromonitoring system, serviceable hearing preservation rate improved from 53 to 77% at our center.

Objective: Some patients with a patulous Eustachian tube (PET) complain of a nasal voice. This feature is often dismissed without further investigation. As such, there are only a few reports on this important symptom and scant studies have been conducted on a sufficiently large number of cases with PET. Therefore, this study was undertaken to investigate the characteristics of patients having a nasal voice and to examine whether this symptom can be an indication of the severity of PET., Study Design: Retrospective., Setting: Tertiary referral center., Subjects and Methods: A retrospective survey of medical records in Sen-En Rifu Hospital identified 85 patients (40 men and 45 women) with PET between 2013 and 2016. Diagnosis of definite PET was based on the Proposal on Diagnostic Criteria of PET announced by the Otological Society of Japan (2017). The questionnaire inquired about the presence of a nasal voice and it was distributed to each patient at the first visit to the clinic. If a patient marked "yes" for the presence of nasal voice, he/she was later asked on the telephone to exclude nasal voice ascribable to causes other than PET, such as nasal diseases. Correlation between nasal voice and patient characteristics (age, sex, affected side, and PET symptoms such as autophony of own voice, aural fullness, and autophony of breathing sounds), subjective severity of PET evaluated by patulous Eustachian tube handicap inventory-10 (PHI-10), and that with the objective severity of PET evaluated by tubo-tympano-aerodynamic-graphy (TTAG) and sonotubometry were investigated., Results: Seventy-six patients (36 men and 40 women) with definite PET were evaluated in this study. Thirteen patients (17.1%) (five men and eight women) reported a nasal voice coinciding with the occurrence of PET symptoms such as voice autophony, aural fullness, and breathing autophony. Age, sex, affected side, PET symptoms (autophony of their own voice, aural fullness, and autophony of their breathing sounds), and objective findings (TTAG and sonotubometry) were not significantly different between the two groups. The average total score of the PHI-10 in the "PET associated Nasal Voice Group" was 35.8 ± 4.5, which was statistically higher than that of the "non PET associated Nasal Voice Group" 23.6 ± 10.7 (p = 0.002). Out of 76 patients, 44 were treated surgically (Kobayashi Plug). In the "PET associated Nasal Voice Group," 85% (11 out of 13) were subjected to surgical treatment, whereas 52% (33 out of 63) underwent surgical treatment in the "non PET associated Nasal Voice Group." The rate of surgical treatment was significantly higher in "PET associated Nasal Voice Group" (p = 0.047)., Conclusion: Nasal voice due to PET symptoms was observed in 17.1% of PET patients. It was generally found in patients with severe subjective symptoms. Nasal voice can be an indication of subjective severity. However, this study failed to show objective evidence of wider Eustachian tube in such cases. Patients with a nasal voice tended to seek vigorous treatment including surgery.

Background: The purpose of this study was to compare orbital blowout fracture sites among different age groups., Methods: This retrospective, observational, comparative study included 671 sides of 663 patients with an orbital blowout fracture. The authors classified patients into five groups based on age (childhood, 0 to 9 years; adolescence, 10 to 18 years; early adulthood, 19 to 44 years; middle adulthood, 45 to 64 years; and late adulthood, 65 years or older); causes of injury into five categories (i.e., sports, traffic accident, assault, fall, and others); and orbital blowout fracture sites into four regions [i.e., the orbital floor lateral (lateral floor) or medial to the infraorbital groove/canal (medial floor); the inferomedial orbital strut (strut); and the medial orbital wall (medial wall)]., Results: A single medial floor fracture was observed in 70.3 percent of patients in the childhood age group. However, the proportion of patients with a single medial wall fracture or multiple fracture sites increased with age. A medial wall fracture was more common than a medial floor fracture in late adulthood. The distribution of orbital blowout fracture sites, the ratio of single or multiple fracture sites, and the causes of injury were statistically different among the age groups (p = 0.005, p = 0.003, and p < 0.001, respectively, Pearson chi-square test)., Conclusions: Common orbital blowout fracture sites varied among age groups. These differences may be attributed to multiple factors, including differences in the morphology of the orbit and paranasal sinuses, composition of the facial bone, and causes of injury among age groups.

Objective: To assess the efficacy of patulous Eustachian tube handicap inventory (PHI) for patulous Eustachian tube (PET) patients., Study Design: Prospective., Setting: Tertiary referral center., Subjects: A prospective survey of medical records in Sen-En Hospital identified 31 ears of 31 patients with definite PET who received insertion of the silicone plug as surgical treatment group, 29 ears of 29 patients treated with self-instillation of physiological saline solution as conservative treatment group, and 29 ears of 29 patients of sensorineural hearing loss without findings of PET treated between June 2015 and December 2015., Method: Diagnosis of definite PET was based on the proposal on PET diagnosis criteria announced by the Otological Society of Japan. The evaluation scale of PHI was modified from the Japanese version of the tinnitus handicap inventory-12 (THI-12). The classification for grading of severity is defined as follows: 1) no handicap (0-8), 2) mild handicap (10-16), 3) moderate handicap (18-24), and 4) severe handicap (26-40), matching the severity grades of tinnitus handicap inventory-25 (THI-25). The outcome measurement was modified from the previous scoring system and is defined as 1) complete relief, 2) significant improvement, 3) slight improvement, 4) unchanged, and 5) worse, and is applied according to the classification for grading of severity. The PHI was conducted at the first visit to our center for all patients in the three groups. For cases requiring surgery for plug insertion, patulous Eustachian tube handicap inventory 10 (PHI 10) was also conducted postsurgery after the treatment (postsurgery)., Results: The findings from questions 1 to 7 and 9 to 11 were significantly different between the surgical (presurgery) and conservative treatment groups (p < 0.05). Taking these results, we analyzed 10 questions excluding questions 8 and 12 (PHI 10). The total score of PHI 10 averaged 19.5 ± 9.3 (n = 31) and 30.6 ± 8.6 (n = 29) in the surgical treatment (presurgery) and conservative treatment groups, respectively, with a significant difference (p < 0.05). Internal consistency reliability testing of the PHI 10 yielded a Cronbach α of 0.887 for all questions. In the surgical treatment (presurgery) and conservative treatment groups, there were 0 (0%) and 3 cases (12%) of no handicap, 3 (10%) and 13 cases (50%) of mild handicap, 6 (19%) and 4 cases (15%) of moderate handicap, and 22 (71%) and 6 cases (23%) of severe handicap, respectively. There was a significant correlation between the PHI 10 and Likert scale (r = 0.796, p < 0.01). In the surgical group, the presurgery and postsurgery PHI 10 scores (n = 25) were 29.6 ± 8.5 and 7.8 ± 11.3, respectively., Conclusion: The PHI 10 is suitable for evaluating severity of PET if the patients have been diagnosed as definite PET. Furthermore, this scoring system could be suitable for surgical treatment assessment.

Backgroud: Pneumocephalus without a known underlying cause is defined as spontaneous pneumocephalus. Few patients of intraventricular pneumocephalus have been reported., Patient Presentation: An 84-year-old man presented with dysarthria and incontinence. Computed tomography revealed an intraventricular pneumocephalus, thinning in the petrous bone, fluid in the air cells, and cleft in temporal lobe. A right subtemporal extradural approach was taken to detect bone-/-dural defects, and a reconstruction was performed using a musculo-pericranial flap., Conclusion: This is the first patient of an isolated intraventricular spontaneous pneumocephalus without any other site air involved. Surgical approaches to repair such bone and dura defects should be considered an appropriate option.

The aim of this study was to examine the superoinferior extension of the post-levator aponeurosis fat pad in the upper eyelids of Japanese cadavers. Twenty-six upper eyelids (12 right and 14 left) from 15 Japanese cadavers (6 men and 9 women; average age at death, 82.1 years) were used in this experimental anatomical study. After an orbital exenteration, the tissues were cut sagittally through the center of the orbit, and the superoinferior extension of the post-levator aponerosis fat pad was microscopically examined on the sections. Consequently, the fat pad superiorly reached the myotendinous junction between the levator aponeurosis and the levator palpebrae superioris (LPS) muscle in 17 eyelids with the nonbranching LPS muscle. The fat pad extended to the roots of the superior and inferior branches of the LPS muscle in the other 9 eyelids with the branching LPS muscle. Inferiorly, the fat pad was limited to the conjunctival fornix in 13 eyelids, but reached the tarsal plate in the other 13 eyelids. This study showed anatomical variation in the superoinferior extension of the post-levator aponerosis fat pad in Japanese cadavers.

Background: Delayed acute subdural hematoma (DASH) is a subdural hematoma which is detected later. An initial computed tomography (CT) does not reveal any intracranial hemorrhage at all. Few patients of DASH after mild traumatic brain injury associated with percutaneous coronary intervention (PCI) have been published., Patient Presentation: A 63-year-old woman presented with cardiac pulmonary arrest due to acute myocardial infarction and lethal arrhythmia. She had hit her head on the road. The initial CT did not reveal any hemorrhage in the intra-cranium. She fully recovered after PCI. However, 1 hour after PCI, she lost consciousness and immediate CT showed acute subdural hematoma and subarachnoid hemorrhage. The period from losing consciousness to brain herniation presenting as anisocoria was very short-only 30 minutes in our patient. Although emergent evacuation of hematoma and external decompression were performed, the patient died 1 day after the operation., Conclusion: The authors encountered a patient of DASH after PCI that resulted in death. Clinicians should be aware that subdural hemorrhage can occur after PCI if no hemorrhage is noted in the initial head CT, and the operation should be performed as soon as possible when the consciousness level decreases., Competing Interests: The authors report no conflicts of interest.

Objectives: Fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV)-coated adenosine 5'-diphosphate-encapsulated liposomes can accumulate via dodecapeptide HHLGGAKQAGDV interactions at bleeding sites where they release adenosine 5'-diphosphate that is rapidly metabolized to adenosine, which has tissue-protective effects. We investigated the efficacy of fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV)-coated adenosine 5'-diphosphate-encapsulated liposomes to treat blast lung injury, with a focus on adenosine signaling., Design: Controlled animal study., Setting: University research laboratory., Subjects: Adult male C57BL/6 mice., Interventions: Mice were pretreated with fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV)-coated adenosine 5'-diphosphate-encapsulated liposomes, dodecapeptide HHLGGAKQAGDV-(phosphate-buffered saline)-liposomes, adenosine 5' diphosphateliposomes, or phosphate-buffered saline-liposomes. Five minutes after treatment the mice received a single laser-induced shock wave (1.8 J/cm) that caused lethal blast lung injury, and their survival times and lung injuries were then assessed. We also evaluated the therapeutic effect of posttreatment with fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV)-coated adenosine 5'-diphosphate-encapsulated liposomes or H12-(phosphate-buffered saline)-liposomes 1 minute after laser-induced shock wave exposure. To examine the effect of adenosine signaling, adenosine A2A receptor (ZM241385) or adenosine A2B receptor (PSB 1115) antagonists were administered to the mice 1 hour before the pretreatment with fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV)-coated adenosine 5'-diphosphate-encapsulated liposomes that was followed by laser-induced shock wave exposure., Measurements and Main Results: Pre- and posttreatment with fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV)-coated adenosine 5'-diphosphate-encapsulated liposomes significantly increased mouse survival [fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV)-coated adenosine 5'-diphosphate-encapsulated liposomes: 58% survival vs H12-(phosphate-buffered saline)-liposomes: 8%; p < 0.05 (posttreatment)] and mitigated pulmonary tissue damage/hemorrhage and neutrophil accumulation after laser-induced shock wave exposure. fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV)-coated adenosine 5'-diphosphate-encapsulated liposomes accumulated at pulmonary vessel injury sites after laser-induced shock wave exposure with both pre- and posttreatment. Furthermore, pretreatment with fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV)-coated adenosine 5'-diphosphate-encapsulated liposomes reduced albumin and macrophage inflammatory protein-2 levels in bronchoalveolar lavage fluid. Although fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV)-coated adenosine 5'-diphosphate-encapsulated liposomes pretreatment did not affect blood coagulation activity in the injured mice, its beneficial effect on blast lung injury was significantly abrogated by A2A or A2B adenosine receptor antagonists (A2A antagonist: 17% survival; A2B antagonist: 33% vs dimethyl sulfoxide control: 80%; p < 0.05, respectively)., Conclusions: Fibrinogen γ-chain (dodecapeptide HHLGGAKQA GDV)-coated adenosine 5'-diphosphate-encapsulated liposomes may be effective against blast lung injury by promoting tissue-protective adenosine signaling and could represent a novel controlled-release drug delivery system.

Objective: To investigate the correlation of sitting 3-D computed tomography (CT) scans of the Eustachian tube (ET) with subjective and objective findings in patients with patulous Eustachian tube (PET)., Study Design: Retrospective., Setting: Tertiary referral center., Subjects: A retrospective survey of medical records in Sen-En Hospital identified 40 patients and 62 ears with PET between September 2014 and June 2015., Method: Diagnosis of PET was based on the presence of three characteristic aural symptoms (autophony of voice or breathing sounds, and aural fullness), as well as verification of synchronous movement of the tympanic membrane in response to forced breathing under an endoscope. Any pressure changes in the external auditory canal (EAC) elicited by deep breathing and sniffing were detected by tubotympanoaerodynamography (TTAG). In addition, sonotubometry was performed where two parameters were used determined to evaluate ET function. Patients were examined by 3-D CT (Accuitomo; Morita, Kyoto, Japan) in the sitting position. The length of the closed ET lumen section was measured. Ears were divided into three groups as follows: completely open, closed-short (3 mm or less), and closed-long (longer than 3 mm)., Results: The median length of the closed section of the ET lumen was 1.85 ± 2.69 mm in positive findings of PET. The three groups were significantly different in both aural fullness (p = 0.023) and, similarly, the difference in tympanic membrane movement (p = 0.032) among these three groups was also significantly different (p = 0.032). However, for autophony of breathing sounds, there was no significant difference with regard to autophony of breathing sounds among these three groups (p = 0.324). Although TTAG findings were did not reveal any significantly difference among these three groups (p = 0.589), the difference was significant (p = 0.001) in degree of EAC pressure change in TTAG. The difference among the three groups was significant (p = 0.001) based on sonotubometry findings., Conclusion: Under resting conditions, the lengths of the closed area of the ETs in PET groups are clearly shorter than in groups without PET based on sitting position CT scans in resting condition. Among the symptoms and clinical test findings including the ET function test results, the presence of tympanic membrane movement induced by respiration, the high degree of EAC pressure change in TTAG, as well as the positive results of sonotubometry are significantly correlated with the positive findings of sitting CT revealing the open ET.

Objective: To examine the objective and subjective outcome of a new transcutaneous bone conduction hearing device., Study Design: Prospective, consecutive case series., Patients: Twelve patients were implanted. Eight patients had a conductive/mixed (con/mix) hearing loss. Four had single sided deafness., Main Outcome Measures: At half-year follow-up, aided and unaided sound field hearing was evaluated by 1) warble tone thresholds, 2) pure-tone average (PTA4), 3) speech discrimination score (SDS) in quiet, and 4) speech reception threshold 50% at 70 dB SPL noise level (SRT50%). Subjective outcome was evaluated by three questionnaires: 1) International Outcome Inventory for Hearing Aids, 2) Speech, Spatial and Qualities of Hearing Scale 12, and 3) a questionnaire on frequency and duration of use., Results: No major complications occurred. The mean aided PTA4 was lowered by 23dB. SDS was increased by 40% at 50dB, by 34% at 65dB, and by 12% at 80 dB SPL. SRT50% in noise improved 5.2 dB. 58% of the patients used the device daily and 83% at least 5 days a week. 50% used the device ≥ 8 hours and 75% ≥ 4  hours a day. Mean International Outcome Inventory for Hearing Aids score was 3.7, corresponding to beneficial outcome. In Speech, Spatial and Qualities of Hearing Scale 12, "quality of hearing" scored especially high. The con/mix hearing loss group showed larger benefit especially in SDS, SRT50% in noise and the subjective evaluations, whereas frequency and duration of use were similar., Conclusion: This study on the first 12 Nordic patients implanted with a new transcutaneous bone conduction hearing device demonstrates significant objective, as well as subjective hearing benefit. Patient satisfaction was high, as was the frequency of use.

Introduction: Programmed death 1 (PD-1) has been reported to be an immunoinhibitory receptor expressed by chronically stimulated T cells after T-cell activation. The present study was designed to evaluate the relationship between perioperative PD-1 expression on CD4 T cells and the incidence of postoperative infectious complications in patients undergoing gastroenterological surgery., Methods: One hundred one patients with gastroenterological disease were enrolled in this study. Blood samples were taken on the preoperative day (Pre) and the first postoperative day (POD1). We calculated the CD4 T-cell count and the PD-1 expression on CD4 T cells via flow cytometry., Results: Postoperative infectious complications occurred in 30 of the 101 patients. The CD4 T-cell count was significantly lower in the patients who developed postoperative infectious complications at POD1 compared with the patients who did not. In addition, the PD-1 expression on CD4 T cells was significantly higher at Pre or POD1 in the patients who developed postoperative infectious complications. The preoperative PD-1 expression on CD4 T cells was found to be independently associated with postoperative infectious complications according to multivariate analysis., Conclusions: The perioperative CD4 T-cell count or PD-1 expression on CD4 T cells may be early predictive markers for the development of postoperative infectious complications.

The double free flap procedure is a preferred treatment for extensive composite defects of the oromandibular area. In this procedure, the choice and use of the flaps are both important. Flaps with adequate soft tissue are required to fill the extensive dead space for huge oromandibular defects. Such flaps, however, tend to sink and droop with time because of gravity, resulting in poor functional and aesthetic results. Here, the authors describe a procedure that avoids flap sinking and drooping, using a vascularized fibular osteocutaneous flap, which is well established for mandibular bone defects, and a rectus abdominalis musculocutaneous flap, which has a lot of soft tissue and a firm anterior rectus sheath. This method was used in 2 patients with extensive composite defects of the oromandibular area. In a patient with resection of the mobile tongue and oral floor, the anterior rectus sheath was fixed to the fibula and mandible to give a mylohyoid muscle-like structure, to prevent sinking of the reconstructed oral floor and tongue. Good swallowing function was maintained. In a patient with defects transversally from the submandibular region to the cheek, the sheath was fixed to the zygomatic arch to prevent cheek drooping. An acceptable aesthetic result was obtained.

Although reactive oxygen species (ROS) basically play beneficial roles to maintain host homeostasis against external disturbance/stress including infection, excessive ROS generation by activated neutrophils can sometimes cause organ damage. We investigated the role of burn-induced ROS generation in the injured hosts, focusing on postburn infection. C57BL/6 mice received a 20% full-thickness burn injury. In these mice, the burn-induced ROS generation was inhibited during and immediately after injury by pretreatment with superoxide dismutase (at 1 h before and immediately before injury), or the subsequent ROS production was inhibited posttreatment with superoxide dismutase (at 1 and 2 h after injury), which could not scavenge the ROS produced immediately after injury. As expected, inhibition of ROS production during/immediately after injury reduced the burn-induced pulmonary damage at 6 h, whereas inhibition of the subsequent ROS production did not lead to any improvements. Burn injury rendered the mice susceptible to bacterial infection at 5 days after injury and impaired bactericidal activity of neutrophils. Nevertheless, inhibition of the ROS production during/immediately after injury did not improve the burn-induced susceptibility to infection or the neutrophil dysfunction. Interestingly, inhibition of the subsequent ROS production potently restored the neutrophil functions and hematopoietic function of the bone marrow myelocytes, thereby improving the postburn infection. Thus, although the inhibition of burn-evoked ROS generation is effective against burn-induced organ injury, it may be ineffective against postburn infection. Preservation of the immediate burn-evoked ROS production, but the inhibition of subsequent ROS production, may be crucial to protect against postburn infection.

Background: Use of a vascularized free fibula flap has become a preferred method of mandible reconstruction after oncologic surgical ablation. Despite its many advantages, the low vertical height of the graft is a potential drawback and severe long-term atrophy of fibular bones may cause stress fracture and is disadvantageous for osseointegrated dental implants and facial contours. Therefore, it is important to investigate the degree of resorption based on the fibular height and the factors related to resorption over time. The influence of aspects of the intraoperative surgical procedure, such as preservation of a nutrient artery from the peroneal artery to the fibula bone marrow and the number of segmental osteotomies, has not been examined previously. Therefore, the purpose of this study was to examine the change in fibular height and the factors influencing resorption, including those associated with the surgical procedure., Patients and Methods: A retrospective analysis was performed in 19 patients who underwent free vascularized fibular mandibular reconstruction for oncologic surgical defects without radiotherapy. Postoperative Panorex examinations were used to evaluate fibular height, and 7 factors with a potential influence on long-term fibular height were evaluated: age, gender, length of the mandible defect, number of segmental osteotomies, preservation of a direct nutrient artery from the peroneal artery to the fibula bone marrow, length of follow-up, and delayed placement of osseointegrated dental implants., Results: Fibular bone height decreased in 13 patients (68%), was unchanged in 2 (11%), and increased in 4 (21%). Segmental osteotomies and female gender were significant factors promoting fibular bone resorption (P < 0.001 and P < 0.001, respectively), and preservation of a nutrient artery to the bone marrow, male gender, and delayed placement of osseointegrated dental implants were significant factors inhibiting bone resorption (P < 0.01, P < 0.001, and P < 0.05, respectively). Age, length of follow-up period, and length of the mandibular defect showed no significant relationship with bone resorption (P = 0.77, P = 0.78, and P = 0.105, respectively)., Conclusion: The results of this study showed that fibular height in mandibular reconstruction can be maintained by preservation of a direct nutrient artery to bone marrow, avoidance of osteotomies, and delayed placement of osseointegrated dental implants, all of which inhibit fibular bone resorption.

An 86-year-old man with iatrogenic eyelid-to-globe malposition had a combination of medial tarsal strip, lateral periosteal sling, and inferior tarsal support with the ear cartilage. An appropriate apposition between the globe and lower eyelid was established postoperatively with good tear meniscus and acceptable cosmetic results.

The objectives of surgical treatment for microstomia due to cicatricial contracture after burn are to obtain sufficient oral aperture, while maintaining sphincter function of the orbicularis oris muscle, and to secure favorable function for eating and conversation in addition to good oral health.The lips of the mouth have a free border, and the oral aperture, which has been enlarged by the operation, tends to be reduced, because of the actions of the orbicularis oris muscle. When the orbicularis oris muscle is resected, putting a priority on sufficient oral aperture and prevention of redevelopment of contracture, the function of the sphincter is often damaged. With the exception of those cases with deep extensive burn that damages a wide area of orbicularis oris muscle, the muscle should be preserved as expeditiously as is practical. In such cases, however, preventive measures for the redevelopment of microstomia should be established. As a postoperative adjuvant therapy, the usefulness of splint therapy has been suggested in many reports. However, a splint should be used for a long period after the surgery, and in some cases, pain is observed with therapy. When a splint is not used for an appropriate period, microstomia may redevelop. It would be ideal to take preventive measures against the redevelopment of contracture during surgery.We provided treatment with some ingenious attempts for the nasolabial flap to a patient with microstomia caused by cicatricial contracture after burn. We obtained favorable results with no postoperative use of a splint.

A large full-thickness defect of the lower lip is difficult to reconstruct. Preservation of eating and speaking functions based on maintenance of oral sphincter and muscle function, sensation, and the oral aperture are the basic aims. It is also important to achieve a good aesthetic appearance. Here, we describe a new procedure using combined bilateral hatchet and nasolabial advancement flaps for a large full-thickness defect of the lower lip. The aim of use of the hatchet flap is to make a natural curve from the mentolabial fold to the mental protuberance using the "dog ear" resulting from suturing medially advanced bilateral hatchet flaps and to preserve a more certain blood supply to the medial edge of the flap. Our results indicate that the procedure using combined bilateral hatchet flaps and nasolabial flaps is useful for a U-shaped large full-thickness defect, with good functional and aesthetic outcomes.

Objective: Variations in the effects of masking noise were evaluated in different pathologies of sensorineural hearing loss., Study Design: Retrospective chart review., Setting: Tertiary referral center., Patients: Fifty-five ears of 30 patients with sensorineural hearing loss who underwent noise audiometry in the Department of Otolaryngology-Head and Neck Surgery, Tohoku University Hospital, since 2010, because of complaints of hearing difficulty in noisy environments., Main Outcome Measures: Masked threshold for narrow band and white noise., Results and Discussion: Masking effects in patients with auditory neuropathy were significantly larger than those in patients with other types of hearing losses. Masking effects of broad band white noise were greater than those of narrow band noise. Masking effects could be observed for white noise even in the elevated unmasked threshold region, where little contribution of excitatory masking effect would be expected. The present findings support the idea that the suppression mechanism caused by normal outer hair cell function is important in the masking phenomenon in patients with auditory neuropathy.

Objective: The study compares the clinical features of patients with congenital cholesteatoma seen in our institution over the most recent 10 years versus those seen in the previous decade. Furthermore, this study includes a systematic review and meta-analysis investigating whether differences in site predilection of congenital cholesteatoma exist between patients from Asian and Western countries., Data Sources: The retrospective review consisted of 31 cases encountered from 2001 to 2011 as compared with 40 cases previously described. For systematic review, data were retrieved from PubMed, EmBase, and the Japan Medical Abstracts Society Database (January 1995 through May 2012)., Study Selections: Articles addressing site predilection of congenital cholesteatoma were selected with no language preference., Data Extraction: The database was searched using the keywords "congenital cholesteatoma." After critical review of 408 studies, 27 studies were eligible for quantitative synthesis., Data Synthesis: A retrospective analysis of our departmental cases showed that more than 70% (8/11) of the Potsic's stage I or II cases had a predilection for the anterior-superior quadrant (ASQ). None of the Stage III (17) or IV (3) cases had a similar site predilection. Consistent with our previous chart review, Stage III was the most common, comprising more than 60% of cases. Meta-analysis of the 27 eligible studies provided sufficient information regarding locations of congenital cholesteatoma, and Asian studies showed less frequent ASQ involvement (overall estimate, 0.54; 95% confident interval [CI], 0.49-0.59) when compared with Western studies (overall estimate, 0.76; 95% CI, 0.73-0.80). Moreover, the involvement of posterior-superior quadrant (PSQ) in Asian studies was estimated as 0.69 (95% CI, 0.64-0.73), which was higher than that associated with involvement of ASQ., Conclusion: In contrast to Western studies, PSQ was more frequently involved than ASQ in Asian studies of congenital cholesteatoma. The posteriorly located lesions might have a completely distinct pathophysiologic origin when compared with lesions originating from the ASQ.

The pectoralis major musculocutaneous (PMMC) flap was once considered the workhorse for head and neck reconstruction; however, because of the proliferation of free tissue transfer, it has rightly taken on a secondary role. Nevertheless, in certain head and neck reconstructions, the PMMC flap remains the last-line treatment and the only salvage option in do-or-die scenarios. The conventional harvesting method of the PMMC flap cuts the lateral thoracic artery and all intercostals branches from the internal mammary vessel to avoid compromising pedicle length. Nonetheless, the dissection of these 2 dominant sources of blood supply to skin islands overlying the lower PMMC flap poses a potentially high risk of distal flap necrosis.To preserve the lateral thoracic vessels, the PMMC flap is a very valid choice from the viewpoint of blood supply. In a novel surgical procedure named "Supercharged Pectoral Major Musculocutaneous Flap"-"SUP-PMMC flap"-devised by us, the lateral thoracic vessels near the bifurcation of subclavian vessels are cut and then anastomosed to the cervical vessels. The procedure causes no vascular insufficiency of skin islands and no compromise to the length of the pedicle and is valid from the viewpoint of blood supply to the lower part of PMMC flaps. The author used this technique in 4 head and neck cancer reconstructions, and no partial flap necrosis or fistula formation was observed.

The authors evaluated the efficacy of an ultrathin nanosheet consisting of poly-L-lactic acid (75 nm thick) as a wound dressing material. A full-thickness skin defect was made on the backs of mice and overlapped with or without the poly-L-lactic acid nanosheet. Wound healing was more rapidly improved by overlapping with the nanosheet, especially in the early healing period (at 4 to 6 days). The remaining wound area in the treatment group was significantly smaller at 4 days than in the control group. Histologically, a clear layer was observed over the granulation layer by the nanosheet therapy at 4 days. Thus, overlapping therapy with the poly-L-lactic acid nanosheet accelerated wound healing and formed a clear layer just above the granulation tissue. The poly-L-lactic acid nanosheet may have potential as a novel wound dressing to promote wound healing.

Ameloblastic carcinoma is a very rare malignant odontogenic tumor. We report a case of secondary-type ameloblastic carcinoma that extended transversally over almost half of the side of the face. Malignant transformation and identification of the malignant region in the large tumor were achieved using L-3-[F]fluoro-α-methyltyrosine (FAMT)-positron emission tomography (PET); FAMT is transported into cancer cells by L-type amino acid transporter 1 and shows high specificity for malignant tumors. The malignant region determined by microscopic evaluation of resected samples was similar to the region showing high FAMT uptake in PET. Using preoperative FAMT-PET and magnetic resonance imaging, we were able to achieve total resection of the very large tumor, while avoiding excessive resection that could cause severe functional loss or a poor aesthetic facial appearance. We used a modified Weber-Fergusson incision along the nasolabial fold to the labiajugal fold and reconstruction with a pectoralis major muscle flap, and this gave a good aesthetic outcome. Safe surgical resection was possible because preoperative three-dimensional computed tomography angiography was used to identify the position of the main trunk of the external carotid artery, which was closely aligned with the tumor in a posterior direction in the infratemporal fossa region.

The objective of the study was to investigate the mechanisms of insufficient interferon-γ (IFN-γ) response to interleukin 18 (IL-18) and the treatment for the insufficient response in septic mice. Interleukin 18 stimulation does not restore IFN-γ production by blood mononuclear cells in septic patients but does restore its production in postoperative patients. Although sepsis impairs the IFN-γ response to IL-18, little is known about why the IL-18/IFN-γ-mediated immune response is ineffective in patients with sepsis. A cecal ligation and puncture was made in C57BL/6 mice following a sublethal lipopolysaccharide challenge to examine their IFN-γ response to IL-18, focusing on natural killer (NK) cells and cytokines. We next examined the effect of neutralization of IL-10 on the NK cell and survival in septic mice. Interleukin 18 injection did not restore IFN-γ production in septic (cecal ligation and puncture) mice. Despite an increase in the numbers of liver NK cells, the IL-18 receptor (IL-18R) expression was decreased in the septic mice compared with sham mice. Serum IL-10 levels were positively correlated with the percentage of liver NK cells, but negatively with their IL-18R expression. Neutralization of IL-10 restored the IL-18R expression on liver NK cells and restored the IFN-γ response in the septic mice, improving their survival. Sepsis might impair IL-18R expression on liver and spleen NK cells and impair the IL-18-mediated IFN-γ response. Neutralization of IL-10 may restore this response in septic hosts, thereby improving survival.

Dietary lipids/cholesterol may modulate liver immune function. We have recently found that mouse F4/80 Kupffer cells are classified into phagocytic CD68 Kupffer cells and cytokine-producing CD11b Kupffer cells. We here investigate how a high-fat and/or high-cholesterol diet affects innate immune liver mononuclear cells. For 4 weeks, C57BL/6 mice were fed a high-fat and high-cholesterol diet (HFCD), a high-cholesterol diet (HCD), a high-fat diet (HFD), or a control diet (CD). High-fat and high-cholesterol diet and HCD increased liver cholesterol levels; serum cholesterol levels increased in HFCD and HFD mice but not in HCD mice. The increased proportion of natural killer (NK) cells, downregulated NK1.1 expression of natural killer T cells, and enhanced CD69 and IL-12 receptor β mRNA expression of liver lymphocytes indicate the activation of them by HFCD. IL-12 production from Kupffer cells and interferon γ production from NK/natural killer T cells activated by LPS and/or IL-12 both increased. IL-12 pretreatment more effectively improved the survival of HFCD mice relative to the survival of CD mice upon injections of liver metastatic EL-4 cells. In contrast, HFCD mouse survival decreased after LPS injection and generalized Shwartzman reaction. Consistently in HFCD mice, Toll-like receptor 4 mRNA expression of whole Kupffer cells was upregulated, and CD11b Kupffer cells proportionally increased. Although the proportion of CD68 Kupffer cells decreased in HFCD mice, phagocytic activity of them was enhanced. Mice fed with HCD rather than those fed with HFD showed features closer to HFCD mice. Thus, enhanced function of mouse liver mononuclear cells is likely dependent on the liver cholesterol level, rather than the liver triglyceride level.

Conduction slowing of the electric impulse that drives the heartbeat may evoke lethal cardiac arrhythmias. Mutations in SCN5A, which encodes the pore-forming cardiac sodium channel alpha subunit, are associated with familial arrhythmia syndromes based on conduction slowing. However, disease severity among mutation carriers is highly variable. We hypothesized that genetic modifiers underlie the variability in conduction slowing and disease severity. With the aim of identifying such modifiers, we studied the Scn5a(1798insD/+) mutation in 2 distinct mouse strains, FVB/N and 129P2. In 129P2 mice, the mutation resulted in more severe conduction slowing particularly in the right ventricle (RV) compared to FVB/N. Pan-genomic mRNA expression profiling in the 2 mouse strains uncovered a drastic reduction in mRNA encoding the sodium channel auxiliary subunit beta4 (Scn4b) in 129P2 mice compared to FVB/N. This corresponded to low to undetectable beta4 protein levels in 129P2 ventricular tissue, whereas abundant beta4 protein was detected in FVB/N. Sodium current measurements in isolated myocytes from the 2 mouse strains indicated that sodium channel activation in myocytes from 129P2 mice occurred at more positive potentials compared to FVB/N. Using computer simulations, this difference in activation kinetics was predicted to explain the observed differences in conduction disease severity between the 2 strains. In conclusion, genetically determined differences in sodium current characteristics on the myocyte level modulate disease severity in cardiac sodium channelopathies. In particular, the sodium channel subunit beta4 (SCN4B) may constitute a potential genetic modifier of conduction and cardiac sodium channel disease.

The pathophysiology of fibromyalgia remains unknown. Several reports have recently suggested the novel concept that fibromyalgia is due to the central nervous system becoming hyper-responsive to a peripheral stimulus. The effect of electroconvulsive therapy (ECT) as pain remedication in cases of fibromyalgia without major depressive disorder was studied in a prospective trial lasting three months. All of the patients taking part in the study fulfilled the American College of Rheumatology diagnostic criteria for fibromyalgia. Technetium-99m ethyl cysteinate dimer single photon emission computed tomography was used to assess regional cerebral blood flow (rCBF) before and after a course of ECT. Pain assessment in the patients was undertaken by use of the visual analog scale (VAS) and by evaluation of tender points (TPs). Beck's depression inventory (BDI) was further used to assess depressive mood change in the patients. Our study clearly demonstrated that pain was significantly less severe after ECT, as indicated by the VAS scale for pain and the evaluation of TPs. A further notable observation was that thalamic blood flow was also improved. We conclude that a course of ECT produced notable improvements in both intractable severe pain associated with fibromyalgia and also in terms of thalamic blood flow.

Recent studies have indicated that caveolae are enriched in a variety of signaling molecules, some of which are associated with cardiomyocyte hypertrophy. Caveolin-3, a major constituent of cardiac caveolae, has been suggested to interact with several signaling molecules. We investigated the morphologic changes of caveolae and caveolin-3 expression in hypertrophied cardiomyocytes induced by an alpha1-adrenergic agonist. Cultured rat neonatal cardiomyocytes were used for the experiments. Phenylephrine induced cellular hypertrophy associated with an increase of the number of caveolae and an up-regulation of caveolin-3. Although PMA increased the number of caveolae and the caveolin-3 expression, the extent of these up-regulations was less than that by phenylephrine. Moreover, ionomycin increased the number of caveolae and up-regulated caveolin-3 as much as phenylephrine. Phenylephrine-induced up-regulations of caveolae and caveolin-3 expression were inhibited by BAPTA, suggesting that the intracellular Ca2+ is involved in those regulations. Inhibitors of calcineurin and Ca2+calmodulin-dependent kinase II attenuated the phenylephrine-induced up-regulation of caveolin-3. In pressure-overloaded rat hearts, caveolin-3 protein levels were increased compared with sham-operated rats. In conclusion, the number of caveolae and the expression of caveolin-3 were up-regulated in rat hypertrophied cardiomyocytes, possibly via the alterations of intracellular Ca2+ and protein kinase C.

Objective: We investigated the comparative roles of mitogen-activated protein (MAP) kinases, including c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38, in vascular smooth muscle cell (VSMC) proliferation, migration, and gene expression., Methods and Results: VSMCs were infected with recombinant adenovirus containing dominant-negative mutants of ERK, p38, and JNK (Ad-DN-ERK, Ad-DN-p38, and Ad-DN-JNK, respectively) to specifically inhibit the respective MAP kinases and then stimulated with platelet-derived growth factor (PDGF)-BB. Ad-DN-ERK attenuated PDGF-BB-induced VSMC proliferation more potently than Ad-DN-p38 or Ad-DN-JNK, indicating the dominant role of ERK in VSMC proliferation. Ad-DN-ERK, Ad-DN-p38, and Ad-DN-JNK similarly inhibited PDGF-induced VSMC migration. Ad-DN-ERK and Ad-DN-JNK suppressed PDGF-BB-induced downregulation of cyclin-dependent kinase inhibitor p27Kip1, whereas Ad-DN-p38 decreased PDGF-BB-induced upregulation of p21Cip1. Ad-DN-ERK inhibited PDGF-BB-induced plasminogen activator inhibitor type-1 (PAI-1), monocyte chemoattractant protein-1, and transforming growth factor-beta1 expressions, Ad-DN-p38 blocked monocyte chemoattractant protein-1 and transforming growth factor-beta1 expression but not PAI-1, whereas Ad-DN-JNK suppressed only PAI-1 expression. Moreover, in vivo gene transfer of Ad-DN-p38 to rat carotid artery caused the inhibition of intimal hyperplasia by balloon injury, indicating the involvement of p38 in vascular remodeling in vivo., Conclusions: We propose that these 3 MAP kinases participate in vascular diseases via differential molecular mechanisms and are new therapeutic targets for treatment of vascular diseases.

Although platelet-derived growth factor (PDGF)-BB is thought to participate in vascular disorders, the mechanism of PDGF-induced vascular smooth muscle cell (SMC) proliferation is not fully understood. This study was undertaken to examine the role of c-Jun in PDGF-BB-induced proliferation of rat aortic SMCs. PDGF-BB (10 ng/mL) significantly increased activator protein (AP)-1 DNA binding activity in SMCs, followed by the increase in [(3)H]thymidine incorporation and cell number. SMCs were infected with recombinant adenovirus containing TAM67, a dominant-negative c-Jun lacking the transactivation domain of wild c-Jun (Ad-DN-c-Jun), to inhibit endogenous AP-1. Ad-DN-c-Jun, which specifically blocked AP-1 transcriptional activity, significantly inhibited PDGF-BB-induced increases in [(3)H]thymidine incorporation or cell number. As shown by flow cytometric analysis, Ad-DN-c-Jun inhibited PDGF-BB-induced entrance of SMCs into S phase, leading to a G(1) arrest. Ad-DN-c-Jun attenuated PDGF-BB-induced downregulation of p27(Kip1), as shown by Western blot analysis, and the prevented PDGF-BB-induced decrease in cyclin E/cyclin-dependent kinase 2 complex-associated p27(Kip1), as shown by immunoprecipitation study. Furthermore, protein kinase assay showed that Ad-DN-c-Jun blocked PDGF-BB-induced activation of cyclin-dependent kinase 2. Our results provide the first evidence that dominant-negative c-Jun inhibits PDGF-BB-induced vascular SMC proliferation by preventing the downregulation of p27(Kip1), thereby supporting the important role of c-Jun in vascular SMC proliferation.

Objective: To determine whether acid instillation augments tumor necrosis factor-alpha and nitric oxide production by alveolar macrophages in rats, and to study the effects of treatment with pentoxifylline before acid instillation on the production of these inflammatory mediators., Design: Controlled laboratory investigation on tumor necrosis factor-alpha and nitric oxide production by alveolar macrophages of rats that had acid-induced lung injury., Setting: University research laboratory., Subject: Alveolar macrophages of rats., Interventions: Alveolar macrophages were recovered by bronchoalveolar lavage at 4, 10, 16, 24, and 72 hrs after unilateral hydrochloric acid (pH, 1.0; volume, 0.1 mL) instillation into the lungs of rats. Alveolar macrophages then were cultured with or without lipopolysaccharide. One group of rats was pretreated with pentoxifylline before acid instillation., Measurements and Main Results: Alveolar macrophages from both acid-instilled and contralateral lungs, which had recovered 24 hrs after acid instillation, produced significantly greater tumor necrosis factor-alpha and nitric oxide. Subsequent exposure to lipopolysaccharide, as a surrogate for bacterial infection, further promoted tumor necrosis factor-alpha and nitric oxide release. Alveolar macrophages from rats pretreated with pentoxifylline before acid instillation produced significantly less tumor necrosis factor-alpha and did not overproduce tumor necrosis factor-alpha when exposed to lipopolysaccharide. In contrast, pretreatment with pentoxifylline had no effect on nitric oxide production by alveolar macrophages., Conclusions: Acid instillation stimulates alveolar macrophages to produce tumor necrosis factor-alpha and nitric oxide. Pentoxifylline preserved innate production of tumor necrosis factor-alpha to lipopolysaccharide and did not inhibit the production of bactericidal nitric oxide. This may partly explain why pentoxifylline reduces acid aspiration-induced lung injury while maintaining the host's ability to combat bacterial infection after acid aspiration.

We previously reported that extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK), belonging to mitogen-activated protein kinases, are rapidly activated in balloon-injured artery. Therefore, we examined the role of these kinase activations in neointimal formation by using an in vivo gene transfer technique. We made the dominant-negative mutants of ERK (DN-ERK) and JNK (DN-JNK) to specifically inhibit endogenous ERK and JNK activation, respectively. Before balloon injury, these mutants were transfected into rat carotid artery using the hemagglutinating virus of Japan liposome method. In vivo transfection of DN-ERK and DN-JNK significantly suppressed the activation of ERK and JNK, respectively, after balloon injury, confirming successful expression of the transfected genes. Neointimal formation at 14 and 28 days after injury was prevented by gene transfer of DN-ERK or DN-JNK. Furthermore, bromodeoxyuridine labeling index and total cell-counting analysis at 7 days showed that either DN-ERK or DN-JNK remarkably suppressed smooth muscle cell (SMC) proliferation in both the intima and the media after injury. Gene transfer of wild-type ERK (W-ERK) or JNK (W-JNK) significantly enhanced neointimal hyperplasia at 14 days after injury. Furthermore, DN-ERK and DN-JNK significantly suppressed serum-induced SMC proliferation in vitro. We obtained the first evidence that in vivo gene transfer of DN-ERK or DN-JNK prevented neointimal formation in balloon-injured artery by inhibiting SMC proliferation. Thus, ERK and JNK activation triggers SMC proliferation, leading to neointimal formation. These kinases may be the new therapeutic targets for prevention of vascular diseases.