Dokkyo Medical University Saitama Medical Center

The authors declare no conflict of interest.

In some cases, laparoscopic cholecystectomy (LC) may be difficult to perform in patients with acute cholecystitis (AC) with severe inflammation and fibrosis. The Tokyo Guidelines 2018 (TG18) expand the indications for LC under difficult conditions for each level of severity of AC. As a result of expanding the indications for LC to treat AC, it is absolutely necessary to avoid any increase in bile duct injury (BDI), particularly vasculo-biliary injury (VBI), which is known to occur at a certain rate in LC. Since the Tokyo Guidelines 2013 (TG13), an attempt has been made to assess intraoperative findings as objective indicators of surgical difficulty; based on expert consensus on these difficulty indicators, bail-out procedures (including conversion to open cholecystectomy) have been indicated for cases in which LC for AC is difficult to perform. A bail-out procedure should be chosen if, when the Calot's triangle is appropriately retracted and used as a landmark, a critical view of safety (CVS) cannot be achieved because of the presence of nondissectable scarring or severe fibrosis. We propose standardized safe steps for LC to treat AC. To achieve a CVS, it is vital to dissect at a location above (on the ventral side of) the imaginary line connecting the base of the left medial section (Segment 4) and the roof of Rouvière's sulcus and to fulfill the three criteria of CVS before dividing any structures. Achieving a CVS prevents the misidentification of the cystic duct and the common bile duct, which are most commonly confused. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

RATIONALE: Acquired pulmonary alveolar proteinosis (PAP) is a syndrome characterized by pulmonary surfactant accumulation occurring in association with granulocyte/macrophage colony-stimulating factor autoantibodies (autoimmune PAP) or as a consequence of another disease (secondary PAP). Because PAP is rare, prior reports were based on limited patient numbers or a synthesis of historical data. OBJECTIVES: To describe the epidemiologic, clinical, physiologic, and laboratory features of autoimmune PAP in a large, contemporaneous cohort of patients with PAP. METHODS: Over 6 years, 248 patients with PAP were enrolled in a Japanese national registry, including 223 with autoimmune PAP. MEASUREMENTS AND MAIN RESULTS: Autoimmune PAP represented 89.9% of cases and had a minimum incidence and prevalence of 0.49 and 6.2 per million, respectively. The male to female ratio was 2.1:1, and the median age at diagnosis was 51 years. A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur. Dyspnea was the most common presenting symptom, occurring in 54.3%. Importantly, 31.8% of patients were asymptomatic and were identified by health screening. Intercurrent illnesses, including infections, were infrequent. A disease severity score reflecting the presence of symptoms and degree of hypoxemia correlated well with carbon monoxide diffusing capacity and serum biomarkers, less well with pulmonary function, and not with granulocyte/macrophage colony-stimulating factor autoantibody levels or duration of disease. CONCLUSIONS: Autoimmune PAP had an incidence and prevalence higher than previously reported and was not strongly linked to smoking, occupational exposure, or other illnesses. The disease severity score and biomarkers provide novel and potentially useful outcome measures in PAP.

BACKGROUND: Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia that is an important risk factor for Parkinson's disease (PD) and Lewy body dementia. Its prevalence is unknown. One barrier to determining prevalence is that current screening tools are too long for large-scale epidemiologic surveys. Therefore, we designed the REM Sleep Behavior Disorder Single-Question Screen (RBD1Q), a screening question for dream enactment with a simple yes/no response. METHODS: Four hundred and eighty-four sleep-clinic-based participants (242 idiopathic RBD patients and 242 controls) completed the screen during a multicenter case-control study. All participants underwent a polysomnogram to define gold-standard diagnosis according to standard criteria. RESULTS: We found a sensitivity of 93.8% and a specificity of 87.2%. Sensitivity and specificity were similar in healthy volunteers, compared to controls or patients with other sleep diagnoses. CONCLUSIONS: A single-question screen for RBD may reliably detect disease, with psychometric properties favorably comparable to those reported for longer questionnaires.

OBJECTIVE: To assess whether risk factors for Parkinson disease and dementia with Lewy bodies increase rate of defined neurodegenerative disease in idiopathic rapid eye movement (REM) sleep behavior disorder (RBD). METHODS: Twelve centers administered a detailed questionnaire assessing risk factors for neurodegenerative synucleinopathy to patients with idiopathic RBD. Variables included demographics, lifestyle factors, pesticide exposures, occupation, comorbid conditions, medication use, family history, and autonomic/motor symptoms. After 4 years of follow-up, patients were assessed for dementia or parkinsonism. Disease risk was assessed with Kaplan-Meier analysis, and epidemiologic variables were compared between convertors and those still idiopathic using logistic regression. RESULTS: Of 305 patients, follow-up information was available for 279, of whom 93 (33.3%) developed defined neurodegenerative disease. Disease risk was 25% at 3 years and 41% after 5 years. Patients who converted were older (difference = 4.5 years, p < 0.001), with similar sex distribution. Neither caffeine, smoking, nor alcohol exposure predicted conversion. Although occupation was similar between groups, those who converted had a lower likelihood of pesticide exposure (occupational insecticide = 2.3% vs 9.0%). Convertors were more likely to report family history of dementia (odds ratio [OR] = 2.09), without significant differences in Parkinson disease or sleep disorders. Medication exposures and medical history were similar between groups. Autonomic and motor symptoms were more common among those who converted. Risk factors for primary dementia and parkinsonism were generally similar, except for a notably higher clonazepam use in dementia convertors (OR = 2.6). INTERPRETATION: Patients with idiopathic RBD are at very high risk of neurodegenerative synucleinopathy. Risk factor profiles between convertors and nonconvertors have both important commonalities and differences.

BACKGROUND: The aim of this study was to report the five scales comprising the rating system that the Japanese Society for Surgery of the Foot (JSSF) devised (JSSF standard rating system) and the newly offered interpretations and criteria for determinations of each assessment item. METHODS: We produced the new scales for the JSSF standard system by modifying the clinical rating systems established by the American Orthopaedic Foot and Ankle Society (AOFAS scales) and the Japanese Orthopaedic Association's foot rating scale (JOA scale). We also provided interpretations of each assessment item and the criteria of determinations in the new standard system. RESULTS: We improved the ambiguous expressions and content in the conventional standard rating systems so they would be easily understood by Japanese people. The result was five scales in total. Four were designed for use specifically for ankle-hindfoot, midfoot, hallux metatarsophalangeal-interphalangeal, and lesser metatarsophalangeal-ineterphalangeal sites; and the fifth was for the foot and ankle with rheumatoid arthritis. Furthermore, we described interpretations and criteria for determinations with regard to evaluation items in each scale. CONCLUSIONS: Conventionally, the AOFAS scales or the JOA scale have been separately applied depending on the sites or disorders concerned, but it was often difficult to decide on scores during practical evaluations because of differing expressions in different languages and also because of ambiguity in the interpretation of each evaluation item and in scoring standards as well. JSSF improved these scales and added definite interpretations of evaluation items as well as criteria for the rating (to be reported here in part I). Because these steps were expected to improve the reliability of outcomes assessed by each scale, we examined the reliability in scores of the newly developed scales, which are reported in part II (in this issue).

Adiponectin (Acrp30), an adipocyte-derived protein, exists in serum as a trimer, a hexamer, and a high-molecular weight (HMW) form, including 12-18 subunits. Because HMW adiponectin may be biologically active, we measured it in serum using a novel enzyme-linked immunosorbent assay (ELISA) confirmed by gel filtration chromatography that the ELISA detected mainly adiponectin with 12-18 subunits, and we compared HMW with total adiponectin concentration in patients with type 2 diabetes. We next investigated the relationship between serum HMW and coronary artery disease (CAD) in 280 consecutive type 2 diabetic patients, including 59 patients with angiographically confirmed CAD. Total adiponectin was measured in serum by a commercially available ELISA. Like serum total adiponectin, HMW adiponectin correlated positively with HDL cholesterol and negatively with triglyceride, insulin sensitivity, creatinine clearance, and circulating inflammatory markers. Total and HMW adiponectin were significantly higher in women than in men, as was the HMW-to-total adiponectin ratio. Serum HMW and the HMW-to-total adiponectin ratio were significantly lower in men with than without CAD (P < 0.05, respectively). In women, the ratio, but neither total nor HMW adiponectin, tended to be lower when CAD was present. In conclusion, determination of HMW adiponectin, especially relative to total serum adiponectin, is useful for evaluating CAD in type 2 diabetic patients.

This study was designed to investigate the therapeutic efficacy of estrogen in female patients with dementia of the Alzheimer type (DAT). Fifteen DAT patients with a mean age of (mean +/- SE) 71.9 +/- 2.4 years were treated with 0.625 mg of conjugated equine estrogens orally twice a day for 6 weeks. Of the 15 DAT patients, 4 were diagnosed as mild, 7 as moderate and 4 as severe. The effects of estrogen on DAT patients were evaluated by psychometric assessments, behavior rating scales, regional cerebral blood flow (rCBF) measurement and quantitative EEG analysis. Psychometric assessments consisted of Mini-Mental State Examination (MMSE) and Hasegawa Dementia Scale (HDS). Dementia syndromes were evaluated by the GBS-Scale (GBSS) and Hamilton Depression Rating Scale (HDRS). During estrogen replacement therapy (ERT), the mean MMSE score (mean +/- SE) increased significantly from 11.6 +/- 1.9 to 13.2 +/- 2.0 at 3 weeks (P < 0.01) and 13.8 +/- 2.0 at 6 weeks (P < 0.001). The mean HDS score increased significantly from 8.6 +/- 2.1 to 11.5 +/- 2.3 at 3 weeks (P < 0.001) and 11.6 +/- 2.6 at 6 weeks (P < 0.01). Significant improvements in the mean scores of the GBSS and HDRS were also observed in the estrogen-treated group, but not in the untreated control group with a mean age of 71.2 +/- 2.5 years (n = 15). The rCBF was measured by single photon emission computed tomography (SPECT). ERT increased the mean rCBF significantly in the lower frontal region (P < 0.01) and primary motor area (P < 0.02) of the right hemisphere. The mean absolute power delta band values in both left and right frontal EEG (Fp1 and Fp2) (P < 0.01) and theta, band values in Fp2 (P < 0.05) decreased significantly during ERT. It is inferred that ERT significantly improves cognitive functions, dementia symptoms, regional cerebral blood flow and EEG activity in female patients with DAT.

Excessive joint surface loadings, either single (acute impact event) or repetitive (cumulative contact stress), can cause the clinical syndrome of osteoarthritis (OA). Despite advances in treatment of injured joints, the risk of OA following joint injuries has not decreased in the past 50 years. Cumulative excessive articular surface contact stress that leads to OA results from posttraumatic joint incongruity and instability, and joint dysplasia, but may also cause OA in patients without known joint abnormalities. In vitro investigations show that excessive articular cartilage loading triggers release of reactive oxygen species (ROS) from mitochondria, and that these ROS cause chondrocyte death and matrix degradation. Preventing release of ROS or inhibiting their effects preserves chondrocytes and their matrix. Fibronectin fragments released from articular cartilage subjected to excessive loads also stimulate matrix degradation; inhibition of molecular pathways initiated by these fragments prevents this effect. Additionally, injured chondrocytes release alarmins that activate chondroprogentior cells in vitro that propogate and migrate to regions of damaged cartilage. These cells also release chemokines and cytokines that may contribute to inflammation that causes progressive cartilage loss. Distraction and motion of osteoarthritic human ankles can promote joint remodeling, decrease pain, and improve joint function in patients with end-stage posttraumatic OA. These advances in understanding of how altering mechanical stresses can lead to remodeling of osteoarthritic joints and how excessive stress causes loss of articular cartilage, including identification of mechanically induced mediators of cartilage loss, provide the basis for new biologic and mechanical approaches to the prevention and treatment of OA.

Background: Current guidelines call for high-intensity statin therapy in patients with cardiovascular disease on the basis of several previous “more versus less statins” trials. However, no clear evidence for more versus less statins has been established in an Asian population. Methods: In this prospective, multicenter, randomized, open-label, blinded end point study, 13 054 Japanese patients with stable coronary artery disease who achieved low-density lipoprotein cholesterol (LDL-C) &lt;120 mg/dL during a run-in period (pitavastatin 1 mg/d) were randomized in a 1-to-1 fashion to high-dose (pitavastatin 4 mg/d; n=6526) or low-dose (pitavastatin 1 mg/d; n=6528) statin therapy. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. The secondary composite end point was a composite of the primary end point and clinically indicated coronary revascularization excluding target-lesion revascularization at sites of prior percutaneous coronary intervention. Results: The mean age of the study population was 68 years, and 83% were male. The mean LDL-C level before enrollment was 93 mg/dL with 91% of patients taking statins. The baseline LDL-C level after the run-in period on pitavastatin 1 mg/d was 87.7 and 88.1 mg/dL in the high-dose and low-dose groups, respectively. During the entire course of follow-up, LDL-C in the high-dose group was lower by 14.7 mg/dL than in the low-dose group ( P &lt;0.001). With a median follow-up of 3.9 years, high-dose as compared with low-dose pitavastatin significantly reduced the risk of the primary end point (266 patients [4.3%] and 334 patients [5.4%]; hazard ratio, 0.81; 95% confidence interval, 0.69–0.95; P =0.01) and the risk of the secondary composite end point (489 patients [7.9%] and 600 patients [9.7%]; hazard ratio, 0.83; 95% confidence interval, 0.73–0.93; P =0.002). High-dose pitavastatin also significantly reduced the risks of several other secondary end points such as all-cause death, myocardial infarction, and clinically indicated coronary revascularization. The results for the primary and the secondary composite end points were consistent across several prespecified subgroups, including the low (&lt;95 mg/dL) baseline LDL-C subgroup. Serious adverse event rates were low in both groups. Conclusions: High-dose (4 mg/d) compared with low-dose (1 mg/d) pitavastatin therapy significantly reduced cardiovascular events in Japanese patients with stable coronary artery disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01042730.

Abstract Background The Japanese Society of Hepato‐Biliary‐Pancreatic Surgery launched the clinical practice guidelines for the management of biliary tract cancers (cholangiocarcinoma, gallbladder cancer, and ampullary cancer) in 2007, then published the 2nd version in 2014. Methods In this 3rd version, clinical questions (CQs) were proposed on six topics. The recommendation, grade for recommendation, and statement for each CQ were discussed and finalized by an evidence‐based approach. Recommendations were graded as Grade 1 (strong) or Grade 2 (weak) according to the concepts of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Results The 31 CQs covered the six topics: (a) prophylactic treatment, (b) diagnosis, (c) biliary drainage, (d) surgical treatment, (e) chemotherapy, and (f) radiation therapy. In the 31 CQs, 14 recommendations were rated strong and 14 recommendations weak. The remaining three CQs had no recommendation. Each CQ includes a statement of how the recommendations were graded. Conclusions This latest guideline provides recommendations for important clinical aspects based on evidence. Future collaboration with the cancer registry will be key for assessing the guidelines and establishing new evidence.

Background and Purpose — Systemic inflammatory response syndrome (SIRS) without infection is a well-known phenomenon that accompanies various acute cerebral insults. We sought to determine whether the initial SIRS score was associated with outcome in subarachnoid hemorrhage (SAH). Methods — In 103 consecutive patients with SAH, the occurrence of SIRS was assessed according to the presence of ≥2 of the following: temperature of &lt;36°C or &gt;38°C, heart rate of &gt;90 bpm, respiratory rate of &gt;20 breaths/min, and white blood cell count of &lt;4000/mm 3 or &gt;12 000/mm 3 . SIRS criteria and other prognostic parameters were evaluated as predictors of dichotomous Glasgow Outcome Scale score. Results — SIRS was highly related to poor clinical grade (Hunt and Hess clinical grading scale), a large amount of SAH on CT (Fisher CT group), and high plasma glucose concentration on admission. By univariate analysis, the occurrence of SIRS was associated with higher mortality and morbidity rates than was the nonoccurrence ( P &lt;0.001). Among individual SIRS criteria, heart rate ( P =0.003), respiration rate ( P =0.003), and white blood cell count ( P =0.03) were significant outcome predictors. By multivariate logistic regression analysis, the presence of SIRS independently predicted outcome. SIRS carried an increased risk of subsequent intracranial complications such as vasospasm and normal pressure hydrocephalus, as well as systemic complications. Conclusions — In SAH patients, SIRS on admission reflected the extent of tissue damage at onset and predicted further tissue disruption, producing clinical worsening and, ultimately, a poor outcome.

BACKGROUND: This study evaluated the validity and inter- and intraclinician reliability of (1) the Japanese Society of Surgery of the Foot (JSSF) standard rating system for four sites [ankle-hindfoot (AH), midfoot (MF), hallux (HL), and lesser toe (LT)] and the rheumatoid arthritis (RA) foot and ankle scale and (2) the Japanese Orthopaedic Association's foot rating scale (JOA scale). METHODS: Clinicians from the same institute independently evaluated participating patients from their institute by two evaluations at a 1- to 4-week interval. Statistical evaluation was as follows. (1) The intraclass correlation coefficient (ICC) was calculated from data collected from at least two examinations of each patient by at least two evaluating clinicians (Data A). (2) Total scores for the two evaluations were determined from the distribution of differences in data between the two evaluations (Data B); each item was evaluated by determining Cohen's coefficient of agreement. (3) The relation between patient satisfaction and total score was investigated only for patients who underwent surgery (Data C). Spearman's rank correlation coefficient was obtained. RESULTS: Participants were 65 clinicians and 610 patients, including those with disorders of the AH (313), MF (47), HL (153), and LT (50) and those with RA (47). From Data A, the ICC was high for AH and HL by JSSF scales and for AH, MF, and LT by the JOA scale. From Data B, the coefficient showed high validity for both scales for AH, with almost no difference between the two scales; the validity for HL was higher with the JOA scale than with the JSSF scale. From Data C, correlations were significant between patient satisfaction and outcome for AH and HL by the JSSF scales and for AH, HL, and LT by the JOA scale. CONCLUSIONS: The validity of both scales was high. Clinical evaluation of the therapeutic results using these scales would be highly reliable.

BACKGROUND: Low-voltage zones (LVZs) represent fibrotic tissue and are substrates for atrial fibrillation (AF). We hypothesized that LVZ-based substrate modification along with pulmonary vein isolation (PVI) would improve outcomes in persistent AF (PeAF) patients with LVZs, whereas PVI alone would work in patients without LVZs. METHODS AND RESULTS: Voltage mapping of the left atrium (LA) was performed during sinus rhythm in 101 PeAF patients in whom LVZ was defined as an area with bipolar electrograms <0.5 mV. Thirty-nine patients had LVZs and underwent ablation of the entire LVZ area after PVI (LVZabl group). In the remaining 62 patients without LVZs, PVI alone was performed with no further substrate modifications (PVI group). An additional group of 16 consecutive PeAF patients with LVZ did not undergo any substrate modification after PVI and were used as a comparison group (LVZnon-abl group) despite having similar size of LVZs to that in the LVZabl group. After a single session, 28 (72%) patients in the LVZabl group had no recurrence, whereas 49 (79%) patients in the PVI group had no recurrence during 18 ± 7 months of follow-up (log-rank, P = 0.400). In the LVZnon-abl group, only 6 patients (38%) had no recurrence during 32 ± 7 months of follow-up, even after a mean number of sessions of 1.8 (log-rank, P < 0.001, compared with the LVZabl group). CONCLUSIONS: Additional LVZ-based substrate modification after PVI improved the outcome in PeAF patients with LVZs, whereas PVI alone worked in patients without LVZs, even in those with PeAF.

Kabuki syndrome is a rare, multiple malformation disorder characterized by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability. Simplex cases make up the vast majority of the reported cases with Kabuki syndrome, but parent-to-child transmission in more than a half-dozen instances indicates that it is an autosomal dominant disorder. We recently reported that Kabuki syndrome is caused by mutations in MLL2, a gene that encodes a Trithorax-group histone methyltransferase, a protein important in the epigenetic control of active chromatin states. Here, we report on the screening of 110 families with Kabuki syndrome. MLL2 mutations were found in 81/110 (74%) of families. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, while a transmitted MLL2 mutation was found in two of three familial cases. The majority of variants found to cause Kabuki syndrome were novel nonsense or frameshift mutations that are predicted to result in haploinsufficiency. The clinical characteristics of MLL2 mutation-positive cases did not differ significantly from MLL2 mutation-negative cases with the exception that renal anomalies were more common in MLL2 mutation-positive cases. These results are important for understanding the phenotypic consequences of MLL2 mutations for individuals and their families as well as for providing a basis for the identification of additional genes for Kabuki syndrome.

CONTEXT: Retinol binding protein (RBP)-4 is a recently identified adipocytokine that is associated with insulin resistance. OBJECTIVES: The aim was to investigate the association between RBP4 and various markers related to insulin resistance and diabetic complications in type 2 diabetic patients. The effect on RBP4 of the addition of pioglitazone to other diabetic medications was also examined. DESIGN, SETTING, PATIENTS, INTERVENTION, AND MAIN OUTCOME MEASURES: RBP4 levels were measured in 101 hospitalized patients with type 2 diabetes and in 22 nonhospitalized control subjects. Endothelial function was evaluated using flow-mediated vasodilatation. In a further 22 nonhospitalized type 2 diabetic patients, pioglitazone (30 mg/d) was administered for 12 wk while other medications for diabetes were continued. RESULTS: There was a significant elevation of RBP4 levels in diabetic patients compared with healthy subjects. RBP4 showed significant positive correlations with triglyceride, systolic blood pressure, and log urinary albumin excretion, and significant negative correlations with high-density lipoprotein cholesterol and flow-mediated vasodilatation. In stepwise regression analysis, log urinary albumin excretion, triglyceride, and gender showed a significant association with RBP4. RBP4 was significantly elevated in patients with proliferative-diabetic retinopathy compared with nondiabetic retinopathy and simple-diabetic retinopathy patients. The addition of pioglitazone for 12 wk to other diabetic medications the patients were already taking did not affect the serum RBP4 concentration. CONCLUSIONS: The current study shows that RBP4 is associated with variables related to insulin resistance and diabetic complications. The addition of pioglitazone for 12 wk to other diabetic medications the patients were already taking did not affect serum RBP4 levels.

THE Pentax-AWS® (Airway Scope; Hoya Corporation, Tokyo, Japan) (fig. 1), an indirect optical laryngoscope invented by a neurosurgeon Jun-ichi Koyama, M.D., Ph.D. (Department of Neurosugery, Shinshu University School of Medicine, Matsumoto, Japan) has been available in Japan since June 2006.1It consists of a disposable blade (PBlade®; Hoya Corporation), a 12-cm image tube with a charge-coupled device camera, and a handle with a 6-cm liquid crystal display (fig. 1). The image tube is inserted into the PBlade® so that the PBlade® completely encloses and protects the image tube and camera. The PBlade® has a transparent window through which the camera obtains images; the camera eye is 3 cm from the tip of the PBlade®.Several studies have shown that the Pentax-AWS® provides full views of the glottis in the majority of patients.2–5There have been several anecdotal reports of successful tracheal intubation using the Pentax-AWS® in patients after failed intubation using a Macintosh laryngoscope.6–9In addition, tracheal intubation using the Pentax-AWS® has been shown to be easier than conventional tracheal intubation in patients whose heads and necks were immobilized to simulate difficult laryngoscopy conditions.5Suzuki et al. recently reported a high success rate of tracheal intubation using the Pentax-AWS® in 45 patients in whom a clear view of the glottis could not be obtained by using a Macintosh laryngoscope.4In their study, no external pressure to the neck was applied during laryngoscopy (to obtain a better view of the glottis), no endotracheal tube introducer was used, and no attempts were made to intubate the trachea with the Macintosh laryngoscope. Therefore, the usefulness of the Pentax-AWS® in patients in whom tracheal intubation using the Macintosh laryngoscope has failed is not known.The main aim of this report was to obtain the success rate of tracheal intubation using the Pentax-AWS® in a large number of patients in whom difficult tracheal intubation using the Macintosh laryngoscope was experienced as a result of a variety of anatomical and pathologic changes. The second aim was to analyze the reasons for difficulty in tracheal intubation with the Pentax-AWS®.We started to use the Pentax-AWS® after it had been licensed for use in clinical practice in 2006. The institutional research ethics committees of all participating institutions approved the study of summarizing data (from October 2006 to August 2008) and reporting the results. The committees stated that the nature of the study would not require written informed consent from each patient. Nine senior anesthesiologists with more than 10-yr experience in anesthesia practice from seven hospitals participated in this project: Kansai Medical University (Takii and Otokoyama Hospitals), Jichi Medical University Hospital, Asahikawa Medical College Hospital, Showa University Hospital, Dokkyo Medical School, Koshigaya Hospital all in Japan, and National University Hospital in Singapore. Each anesthesiologist had practiced the Pentax-AWS® in mannequins and had used the device in more than ten patients without predicted difficult airways.We prospectively collected cases of the Pentax-AWS® in two groups of patients. In patients in whom orotracheal intubation was indicated, we used a Macintosh laryngoscope after induction of general anesthesia and neuromuscular blockade, when neither difficult tracheal intubation nor difficult mask ventilation was predicted, or when difficult tracheal intubation was predicted but difficult mask ventilation was not predicted. We used the Pentax-AWS® when tracheal intubation using a Macintosh laryngoscope had been difficult (group 1). If both difficult tracheal intubation and difficult mask ventilation were predicted, we used the Pentax-AWS® (before induction of anesthesia and before neuromuscular blockade) without previous use of the Macintosh laryngoscope (group 2). We did not include patients in whom we had used the Pentax-AWS® for insertion of double-lumen tubes or bronchial blockers or for the exchange of tracheal tubes. Patients in whom nasotracheal intubation was required were also not included. To obtain a success rate of tracheal intubation with the Pentax -AWS®, we included 14 patients who have been reported previously.4,6,8,10,11We recorded the patients’ characteristics, preoperative view of the oropharynx (classification according to Mallampati et al. 12and Samsoon and Young13), and the thyromental distance, and we predicted that tracheal intubation using a Macintosh laryngoscope would be difficult when Mallampati was 3 or 4, when the thyromental distance was less than 6 cm, or when the patient was severely or very severely obese (as 35.0 kg/m2or greater, according to the World Health Organization classification). We also recorded the presence of any other factors that might make tracheal intubation difficult.In the operating room, we monitored all patients with electrocardiography, pulse oximetry, and noninvasive blood pressure. The patient’s head was placed on a pillow (height, 4–7 cm) unless there was a risk of cervical spinal cord injury. When there was a risk of cervical spinal cord injury, the patient’s head was placed directly on the operating table, and the head and neck were stabilized either manually or by a stabilizer, such as a Halo vest.After preoxygenation of the patient, we induced anesthesia with either propofol or thiopental. After we had confirmed adequate ventilation with a facemask, we produced a neuromuscular blockade with either vecuronium or atracurium. Each anesthesiologist attempted to intubate the trachea by using a conventional English-type Macintosh laryngoscope. We judged that tracheal intubation using the Macintosh laryngoscope was difficult when one of the participating senior anesthesiologists failed to intubate the trachea twice (with external pressure to the neck and with or without the use of an Eschmann endotracheal tube introducer) or when the senior anesthesiologist would have considered an alternative device (such as the McCoy laryngoscope, intubating laryngeal mask airway, or flexible bronchoscope) had the Pentax-AWS® not been available. When a senior anesthesiologist was called by a junior who had failed to intubate the trachea using a Macintosh laryngoscope, the senior anesthesiologist could limit the insertion of the Macintosh laryngoscope to only one attempt to minimize repeated attempts at laryngoscopy.When the anesthesiologist judged that tracheal intubation was difficult, tracheal intubation using the Pentax-AWS® was attempted. We prepared the Pentax-AWS® system by attaching the PBlade® to the handle and fitting a well-lubricated endotracheal tube (either a conventional polyvinylchloride tube or reinforced tube) into the tube groove on the PBlade®. We positioned the endotracheal tube such that its tip was just visible on the liquid crystal display screen without obstructing views of the airway (fig. 2). The PBlade® was inserted orally, with its tip toward the glottic side of the epiglottis, as with a Miller laryngoscope blade. We used the target symbol on the display to optimize alignment of the PBlade® with the glottis to facilitate insertion of the endotracheal tube.We graded the laryngoscopy views for each device using a modified classification reported by Cormack and Lehane.14We made these modifications because the tip of the Pentax-AWS PBlade® is inserted toward the glottis (table 1). Nevertheless, the grading for the Macintosh laryngoscope with this modified method should be the same for the original grading reported by Cormack and Lehane.14After obtaining a view of the glottis, we attempted to advance an endotracheal tube into the trachea, and we confirmed correct tracheal intubation by auscultation of the chest and by capnography. During the period of data collection, we noticed that the use of the Eschmann endotracheal tube introducer (SIMS Portex; Hythe, Kent, United Kingdom) might be useful to guide an endotracheal tube if there was difficulty in aligning the PBlade® with the glottis.11Since that time, if there was difficulty in advancing a tube into the trachea, each anesthesiologist was allowed to use the Eschmann tube introducer to guide entry of the endotracheal tube into the trachea. In brief, the introducer was passed through the endotracheal tube that was loaded on the PBlade®, and the angulated tip of the introducer was directed toward the glottis under vision. After insertion of the introducer into the trachea, the tube was advanced over the introducer into the trachea.We allowed up to two attempts with the Pentax-AWS®. Nevertheless, we abandoned its use if we judged that there was a high risk of trauma to the airway or if arterial hemoglobin oxygen saturation decreased to less than 95%. In such a case, we used an alternative device, such as a flexible bronchoscope. We recorded the number of attempts at tracheal intubation and the use of the Eschmann tube introducer. Due to ethical considerations, if it was impossible to see the glottis (particularly if the epiglottis was not seen), the anesthesiologist could judge that tracheal intubation had failed even when an endotracheal tube introducer or an endotracheal tube was not actually inserted. No patients were excluded from the data analyses after the Pentax-AWS® was used. Possible causes of difficult tracheal intubation with the Macintosh laryngoscope and with the Pentax-AWS® were recorded.In group 2, we used the Pentax-AWS® without previous use of the Macintosh laryngoscope in patients in whom both tracheal intubation and mask ventilation were predicted to be difficult.As in group 1, the patient’s head was placed on a pillow (height, 4–7 cm) unless there was a risk of cervical spine injury. When there was a risk of cervical spinal cord injury, the patient’s head was placed directly on the operating table, and the head and neck were stabilized either manually or by a stabilizer, such as a Halo vest. Each anesthesiologist decided to give local anesthetics, sedatives, or analgesics on the basis of the patient’s condition. After preoxygenation of the patient, the Pentax-AWS® was inserted and up to two attempts were made to intubate the trachea. If it was impossible to intubate the trachea, alternative methods, such as fiberoptic intubation or tracheotomy, were used to secure the airway. The number of attempts at tracheal intubation and types of local anesthetics, sedatives, or analgesics used were recorded.The means and standard deviations of patients age, height, weight, and body mass index were calculated. The 95% confidence intervals (CI) for the proportion of having a clear view of the glottis (Cormack and Lehane grade 1 or 2) and the success rate of tracheal intubation using the Pentax-AWS® were calculated. Minitab release 13 (State College, PA) was used to for statistical analyses.We used the Pentax-AWS® in 270 patients in whom laryngoscopy using a Macintosh laryngoscope had failed; characteristics are reported in table 2. The main predisposing factors (detected preoperatively) that made tracheal intubation using the Macintosh laryngoscope difficult included restricted neck movement (90 patients), Mallampati score 3 or 4 (91 patients), thyromental distance less than 6.0 cm (70 patients), retrognathia (56 patients), difficulty in opening the mouth (36 patients), and history of difficult intubation (19 patients) (table 3). Other factors included macrognathia (3 patients), pharyngeal tumor (2 patients), laryngeal tumor (1 patient), lingual tonsillar hypertrophy (1 patient), severe sleep apnea syndrome (1 patient), postpharyngectomy (2 patients), epiglottic cyst (2 patients), distortion of the larynx by a thyroid tumor (1 patient), scoliosis (1 patient), history of polio (1 patient), Treacher-Collins syndrome (1 patient), Crouzon syndrome (1 patient), Goldenhar syndrome (3 patients), and Marfan syndrome (1 patient). No predisposing factors were found in 59 patients.The Cormack and Lehane grades of glottis view at laryngoscopy with the Macintosh laryngoscope are detailed in table 4. In 39 patients, it was not possible to elevate the epiglottis by a Macintosh blade sufficiently enough to expose the glottis. In 256 patients in whom the grade was 3 or 4 with the Macintosh laryngoscope, the view with the Pentax-AWS® was either grade 1 or 2 in 255 patients (99.6%; 95% CI 97.8–100%).Tracheal intubation was successful with the Pentax-AWS® in 268 of 270 patients (99.3%; 95% CI 97.4–100%) (table 5). It was successful (without the use of the Eschmann endotracheal tube introducer) at the first attempt in 255 of 270 patients (94.4%), at the second attempt in 13 patients (4.8%; in seven and six patients with and without the aid of the Eschmann tube introducer, respectively). The success rate of tracheal intubation without the use of the Eschmann tube introducer was 96.7% (261 of 270 patients; 95% CI 93.8–98.5%).In these two patients in whom tracheal intubation failed, it was impossible to maneuver the PBlade® of the Pentax-AWS® toward the glottic side of the epiglottis, and the glottis could be seen in one patient (grade 1) and it could not be seen (grade 3) in the other patient. In both patients, an Eschmann tube introducer was not used, and the epiglottis prevented insertion of an endotracheal tube. In these patients, the trachea was intubated with difficulty by using a fiberoptic bronchoscope.The reasons for failed tracheal intubation using the Pentax-AWS® after the first attempt (in 15 patients) included failing to align the PBlade® to the glottis (9 patients), failing to elevate the epiglottis sufficiently (5 patients), and tongue obstruction of PBlade® insertion due to retrognathia and restricted jaw movement (1 patient). There were predisposing factors for difficult tracheal intubation in 13 of 15 patients, and no predisposing factors were detected in the remaining two patients. Predisposing factors included restricted head and neck movement (5 patients), retrognathia (4 patients), short thick neck (2 patients), severely or very severely obese (2 patients), and difficulty in mouth opening (1 patient).In group 2, we electively used the Pentax-AWS® in 23 patients with known or predicted difficult tracheal intubation and mask ventilation (tables 2, 3). The factors predicting difficult airway management included Mallampati grade 3 or 4 (14 patients), difficulty in mouth opening (4 patients), thyromental distance less than 6 cm (12 patients), retrognathia (3 patients), and restricted neck movement (15 patients), deformity of the airway by a tumor or by radiation (2 patients), large pharyngeal tumor (1 patient), large epiglottic cyst (1 patient), and postcarotid endarectomy bleeding (1 patient) (table 3).Local anesthetics (lidocaine spray), sedatives, or analgesics were used in 21 patients, whereas none were used in the other two patients. For sedation, either midazolam (2–3 mg) plus fentanyl (50–100 μg) or remifentanil (0.1 mg · kg–1· h–1) was used. Incremental 10-mg doses of propofol were also used.Tracheal intubation using the Pentax-AWS® was successful in 22 of 23 patients. It was successful at the first attempt in 20 patients and at the second attempt in 2 patients, and it failed in 1 patient (table 5). This patient in whom tracheal intubation failed had required airway management and anesthesia for emergency surgery to stop postcarotid endarterectomy bleeding. The bleeding was causing airway obstruction. No clear view of the glottis was obtained with the Pentax-AWS® due to tissue swelling and blood in the oropharynx. The patient needed an emergency tracheostomy after failed intubation with the Pentax-AWS®.We have found that the success rate of tracheal intubation using the Pentax-AWS® was high in patients in whom tracheal intubation with the Macintosh laryngoscope had been difficult, as well as in patients with known or predicted difficult laryngoscopy, mask ventilation, or both.Suzuki et al. reported a high success rate of tracheal intubation using the Pentax-AWS® in 45 patients in whom a clear view of the glottis could not be obtained (Cormack and Lehane grade 3 or 4) using a Macintosh laryngoscope.4In their study, no external pressure to the neck was applied during laryngoscopy (to obtain a better view of the glottis), no endotracheal tube inroducer was used, and no attempts were made to intubate the trachea with the Macintosh laryngoscope. Because the reasons for difficult laryngoscopy and difficult tracheal intubation vary considerably between patients, a large number of patients with a variety of anatomical or pathologic changes to the airway would be required to assess the usefulness of any intubation device. We assessed the usefulness of the Pentax-AWS® in a large number of patients with difficult airways due to several different pathologic changes, such as restricted neck movement, deformity of the airway, tumors in the airways, and postendarectomy bleeding. Our results indicate that the Pentax-AWS® is potentially useful in patients with difficult airways due to several different pathologic changes.Indirect-optical laryngoscopes or videolaryngoscopes represent a major technological advancement in anesthesia practice.15–17The image of the glottis is captured near the tip of the laryngoscope; as a result, the glottis will be just a few centimeters from the “eye.” Unlike conventional direct laryngoscopes, it is unnecessary to align the laryngeal, pharyngeal, and oral axes to view the glottis with videolaryngoscopes. Therefore, there is theoretically a higher likelihood of obtaining a full view of the glottis even when head and neck movement are restricted. In our patients, the Pentax-AWS® enabled good views of the glottis (Cormack and Lehane grade 1 or 2) in 255 of 256 patients (99.6%) in whom laryngoscopy view were grade 3 or 4 with a Macintosh laryngoscope.There have been several reports of successful use of other videolaryngoscopes, such as GlideScope or TruView, in patients with difficult airways in whom tracheal intubation with a Macintosh laryngoscope had failed.15–17One major limitation of these videolaryngoscopes is that, even when a clear view of the glottis is obtained, it can be difficult to direct the endotracheal tube into view and into the trachea.18,19In contrast, there is no difficulty in locating the tube tip with the Pentax-AWS® because the tip of an endotracheal tube is already captured on the video screen before device insertion (fig. 2). The target symbol on the liquid crystal display screen enables optimal alignment of the PBlade® and loaded endotracheal tube with the glottis. The PBlade® design is such that it guides the loaded endotracheal tube toward the glottis when the tube is advanced down the PBlade tube groove, thus enabling a smooth tracheal intubation (fig. 1).In our study, tracheal intubation was successful in 268 of 270 patients (99.3%) with difficult Macintosh laryngoscopy, and tracheal intubation failed in only two of these patients (0.7%). It is not possible to calculate the incidence of difficult intubation using the Pentax-AWS® in general population because we do have the denominator for the incidence of difficult laryngoscopy with Macintosh laryngoscopes. One has shown that the incidence for difficult laryngoscopy with a Macintosh laryngoscope (grade 3 or 4) is CI we that the incidence of difficult laryngoscopy with the Macintosh blade at our hospitals was also we can calculate the incidence of difficult laryngoscopy with the Pentax-AWS® in the general which is 1 in neck movement is one major of difficulty in the glottis with a Macintosh laryngoscope. In our tracheal intubation was successful with the Pentax-AWS® in of patients who had restricted neck movement or who needed to cervical spinal cord injury. This high glottis success rate is because there is no to the head and neck in the with the with the Macintosh laryngoscope. studies have also shown less neck movement during laryngoscopy with the Pentax-AWS® to with a Macintosh a study of laryngoscopy during the of the cervical spine in patients without neck the view of the glottis was (Cormack and Lehane grade 3 or 4) in 22 patients with a Macintosh laryngoscope, whereas a full view of the glottis (Cormack and Lehane grade 1) was obtained with the Pentax-AWS® in all results the of the Pentax-AWS® for laryngoscopy and tracheal intubation in patients with cervical spine patients, of tracheal intubation with a Macintosh laryngoscope was the result of epiglottic laryngeal and deformity of the The Pentax-AWS® tracheal intubation in these patients. We have found that the Pentax-AWS® was useful in these patients because it was easier to the pathologic changes than with the Macintosh laryngoscope and because it was easier to that the tube was not the pathologic changes. The Pentax-AWS® was also useful in patients with several different such as Treacher-Collins syndrome and Crouzon Therefore, the number of patients with each pathologic was the Pentax-AWS® to be useful in patients with difficult airways due to a variety of anatomical or pathologic we had high success of laryngoscopy with the there be several to its an we found that there might be difficulty in advancing the endotracheal with the tip of the endotracheal tube on the or the epiglottis, obtaining a clear view of the glottis. In our study, this was the main of difficulty in our patients (9 of 15 We have found that it was useful to an endotracheal tube introducer through the endotracheal tube into the trachea and advance the tube over the used this in seven patients, and it was In our tracheal intubation in one patient failed after two In this patient, the anesthesiologist did not use the introducer to guide the second limitation is the difficulty in the PBlade® tip toward the glottic or of the In this the epiglottis the insertion of the endotracheal tube into the trachea when it is advanced down the PBlade®. This can also be by an introducer through the endotracheal tube into the trachea, the tube from the PBlade®, and advancing the endotracheal tube over the introducer into the trachea. The can be on the Pentax-AWS®. it be difficult to the PBlade® in patients with mouth it was possible to the PBlade® in one patient with distance of cm, and tracheal intubation was successful at the first the PBlade® is only available in one and is not for The PBlade® can tracheal tubes up to and it be used with double-lumen with other videolaryngoscopes and with flexible in the and of the PBlade® window can failed laryngoscopy with the Pentax-AWS®. into the oropharynx in one patient after endarterectomy failed laryngoscopy and intubation with the Pentax-AWS®. The PBlade® has a through which a can be passed to blood and to the PBlade® can also be inserted into the oral to the Pentax-AWS® is used. of the PBlade® window can be by an to the window or by the PBlade® in before its limitation of this study is that there might have been of patients. each anesthesiologist might have decided using the Pentax-AWS® if its use was predicted to be difficult, for when mouth opening was severely or when there was a large mass in the oral we did not include patients who required nasotracheal intubation or tracheal bronchial tubes. we did not include patients who were at risk of Therefore, the and incidence of failed tracheal intubation with the Pentax-AWS® in patients with difficult airways is not because of the nature of the study, we used the Pentax-AWS® after tracheal intubation using the Macintosh laryngoscope had failed in group If the of intubation had been the results could have been Nevertheless, the difficulty in tracheal intubation would after repeated attempts at the success rate of tracheal intubation using the Pentax-AWS® would not have decreased if it had been used before insertion of the Macintosh the success rate of tracheal intubation using the Pentax-AWS® was high in patients with difficult tracheal intubation with a Macintosh laryngoscopy due to variety of different anatomical or pathologic reasons and in patients with known or predicted difficult

OBJECT: Magnetic resonance (MR) imaging now permits diagnosis of increasing numbers of small, minimally symptomatic vestibular schwannomas (VSs). Because VS growth patterns over time are very important in refining treatment strategies, these matters were systematically reviewed. METHODS: An extensive MEDLINE search was performed to cull studies on VS growth according to sequential imaging. The percentages of growing and regressing tumors and lesions requiring treatment during follow-up periods were calculated. Factors associated with differences among studies were identified. Twenty-six studies including 1340 patients met all inclusion criteria. The overall frequency of VS growth during a mean follow-up period of 38 months was 46% (95% confidence interval [CI] 43-48%) and that of regression was 8% (95% CI 6-10%). The mean annual tumor growth rate was 1.2 mm/year. Furthermore, the percentage of cases requiring treatment during follow up was 18% (95% CI 16-21%). According to results of a sensitivity analysis, evaluation by serial MR imaging (39%, 95% CI 35-43%) and a prospective study design (29%, 95% CI 21-37%) were associated with less frequent reported tumor growth. CONCLUSIONS: Although their applicability may be limited to relatively elderly patients with small tumors, data revealing a limited frequency of VS enlargement and an infrequent necessity for eventual therapy should assist decision-making in the treatment of small VSs causing minimal symptoms.

1 The objective was to determine the role of muscarinic receptor subtypes in mediating contraction of the human detrusor smooth muscle in vitro. 2 Contractile responses of human detrusor muscle strips to carbachol were obtained in the absence and presence of a range of muscarinic antagonists (pirenzepine, methoctramine, 4-diphenylacetoxy-N-methyl piperidine methiodide (4-DAMP), tropicamide, oxybutynin and tolterodine). Affinity estimates (pKB values) were calculated for the antagonists and correlated with values at the cloned muscarinic receptor subtypes quoted in the literature. 3 Pirenzepine, methoctramine and tropicamide drugs that have high affinities at M1, M2 and M4-receptors, respectively, all had low affinities on the human detrusor (pKB values of 6.8, 6.9 and 6.5, respectively), whilst the M3-selective antagonist 4-DAMP had a high affinity (9.5). Schild plots for all four antagonists had slopes of unity indicating an action at a single receptor. Oxybutynin and tolterodine also acted as competitive antagonists with affinity estimates of 7.6 and 8.1, respectively. 4 When the antagonist affinities obtained on the bladder were plotted against the values published for these antagonists at the cloned muscarinic receptor subtypes, the best correlations were obtained for the m3- and m5-muscarinic receptor subtypes. 5 These data suggest that direct contractile responses of the human detrusor muscle to muscarinic receptor stimulation in vitro are mediated solely via the M3-muscarinic receptor subtype with no contribution from the major M2-receptor population.

Kabuki syndrome is a congenital anomaly syndrome characterized by developmental delay, intellectual disability, specific facial features including long palpebral fissures and ectropion of the lateral third of the lower eyelids, prominent digit pads, and skeletal and visceral abnormalities. Mutations in MLL2 and KDM6A cause Kabuki syndrome. We screened 81 individuals with Kabuki syndrome for mutations in these genes by conventional methods (n = 58) and/or targeted resequencing (n = 45) or whole exome sequencing (n = 5). We identified a mutation in MLL2 or KDM6A in 50 (61.7%) and 5 (6.2%) cases, respectively. Thirty-five MLL2 mutations and two KDM6A mutations were novel. Non-protein truncating-type MLL2 mutations were mainly located around functional domains, while truncating-type mutations were scattered through the entire coding region. The facial features of patients in the MLL2 truncating-type mutation group were typical based on those of the 10 originally reported patients with Kabuki syndrome; those of the other groups were less typical. High arched eyebrows, short fifth finger, and hypotonia in infancy were more frequent in the MLL2 mutation group than in the KDM6A mutation group. Short stature and postnatal growth retardation were observed in all individuals with KDM6A mutations, but in only half of the group with MLL2 mutations.