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Objective: To analyze the time trends of recidivism of acquired cholesteatoma using the Kaplan-Meier method., Study Design: We conducted a retrospective, observational study of 256 patients having their first cholesteatoma surgery. The cumulative recidivism-free rate was calculated using Kaplan-Meier survival analysis related to the follow-up period, pathophysiology, the extent of the disease, and recidivism pathologies., Results: Pars flacida cholesteatoma with tympanic cavity progression had a high likelihood of recurrence disease. Pars tensa cholesteatoma led to more recurrence of the disease than the residual disease. In both pars flacida and pars tensa cholesteatoma, the incidence of disease recurrence increased even 3 years after surgery. On the contrary, the incidence of residual disease peaked within 3 years after surgery, and thereafter, the incidence of residual disease tended to be small. In particular, pars flacida cholesteatoma extending into the mastoid cavity or tympanic cavity tended to recur up to 5 years postoperatively., Conclusions: We calculated the cumulative recidivism-free rates of 256 patients with cholesteatoma using Kaplan-Meier survival analysis. These results can lead to better estimates of the length of the follow-up period., Level of Evidence: Level IV evidence from case-control studies., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2023, Otology & Neurotology, Inc.)

Objective: Cholesteatoma is occasionally accompanied by excessive calcification and presumably has different osteogenic dynamics compared to noncholesteatomous chronic otitis media. Cholesteatoma-related sclerotic lesions through the temporal bone can pose manipulatory difficulties, possibly leading to worse surgical outcomes or complications. Therefore, we compared surgical outcomes of cholesteatomas with and without sclerotic lesions., Study Design: Retrospective cohort study., Setting: Tertiary academic medical center., Patients: Consecutive ears with acquired cholesteatomas requiring primary resection between January 2009 and December 2019. The ears followed up for <1 year were excluded., Interventions: Tympanoplasty with/without mastoidectomy., Main Outcome Measures: Prevalence and location of sclerotic lesion, comorbid fistulae, postoperative air-bone gap, recidivism, and complications., Results: Overall, 19 (6.4%) of 299 ears had sclerotic lesions. More than two-thirds (68.4%) of sclerotic lesions were located adjacent to the lateral semicircular canal (LSC). Among ears with sclerotic lesions adjacent to the LSC, 46.2% had a comorbid fistula in the LSC. The prevalence of labyrinth fistula was significantly greater in ears with sclerotic lesions (42.1%) than in ears without sclerotic lesions (5.0%) (p < 0.0001, Fisher's exact test). Sensorineural hearing deterioration was significantly higher in ears with sclerotic lesions than in ears without (p = 0.0004, Fisher's exact test). Multivariate logistic regression analysis demonstrated that the presence of sclerotic lesions was a significant prognostic factor for residual disease (odds ratio [95% confidence interval]: 6.820 [2.055-22.633], p = 0.0017)., Conclusions: Surgeons should be conscious of preoperative identification of sclerotic lesions adjacent to one of the semicircular canals, possibly leading to postoperative sensorineural hearing deterioration or residual cholesteatoma., Competing Interests: The authors disclose no conflicts of interest. The authors alone are responsible for the content and writing of the manuscript., (Copyright © 2022, Otology & Neurotology, Inc.)

Objectives: Recurrent middle-ear infection can lead to ossicular fixation, adversely affecting post-tympanoplasty hearing outcomes. Preoperative prediction of ossicular fixation remains challenging. We aimed to investigate potential predictors of ossicular fixation in patients with chronic otitis media., Study Design: Retrospective., Setting: Tertiary academic medical center., Patients: Patients with noncholesteatomatous chronic otitis media and tympanic membrane perforation, without ossicular discontinuities., Interventions: Diagnostic., Main Outcome Measures: The fixation of each ossicle was assessed during tympanoplasty. The impact of preoperative otoscopic findings, computed tomography (CT) features, and hearing levels on the prediction of ossicular fixation was evaluated using uni- and multivariable logistic regression analyses., Results: One hundred thirty-five patients were included. Soft-tissue density between the malleus head and the anterior wall (odds ratio, 3.789 [95% confidence interval, 1.177-12.196]; p = 0.0255) and poor development of mastoid cells (16.826 [2.015-134.520]; p = 0.0078) were independent predictors of malleus fixation. In addition, ≥50% tympanic membrane perforation (5.412 [1.908-15.353]; p = 0.0015), poor development of mastoid cells (3.386 [1.039-11.034]; p = 0.0431), and a ≥40-dB preoperative air-bone gap (ABG) at 500 Hz (4.970 [1.732-14.261]; p = 0.0029) were independent predictors of incus fixation. Soft-tissue density surrounding the stapes (18.833 [1.856-191.104]; p = 0.0119) and a ≥40-dB preoperative ABG at 500 Hz (13.452 [1.640-∞]; p = 0.0138) were correlated with stapes fixation., Conclusions: The accurate prediction of ossicular fixation in patients with chronic otitis media based on CT features and the ABG may facilitate decision-making regarding the need for ossiculoplasty, possibly avoiding unnecessary manipulation or overlooking of fixation., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2021, Otology & Neurotology, Inc.)

Abstract: To avoid ventilator-associated lung injury in acute respiratory distress syndrome (ARDS) treatment, respiratory management should be performed at a low tidal volume of 6 to 8 mL/kg and plateau pressure of ≤30 cmH2O. However, such lung-protective ventilation often results in hypercapnia, which is a risk factor for poor outcomes. The purpose of this study was to retrospectively evaluate the effectiveness and safety of the removal of a catheter mount (CM) and using heated humidifiers (HH) instead of a heat-and-moisture exchanger (HME) for reducing the mechanical dead space created by the CM and HME, which may improve hypercapnia in patients with ARDS.This retrospective observational study included adult patients with ARDS, who developed hypercapnia (PaCO2 > 45 mm Hg) during mechanical ventilation, with target tidal volumes between 6 and 8 mL/kg and a plateau pressure of ≤30 cmH2O, and underwent stepwise removal of CM and HME (replaced with HH). The PaCO2 values were measured at 3 points: ventilator circuit with CM and HME (CM + HME) use, with HME (HME), and with HH (HH), and the overall number of accidental extubations was evaluated. Ventilator values (tidal volume, respiratory rate, minutes volume) were evaluated at the same points.A total of 21 patients with mild-to-moderate ARDS who were treated under deep sedation were included. The values of PaCO2 at HME (52.7 ± 7.4 mm Hg, P < .0001) and HH (46.3 ± 6.8 mm Hg, P < .0001) were significantly lower than those at CM + HME (55.9 ± 7.9 mm Hg). Measured ventilator values were similar at CM + HME, HME, and HH. There were no cases of reintubation due to accidental extubation after the removal of CM.The removal of CM and HME reduced PaCO2 values without changing the ventilator settings in deeply sedated patients with mild-to-moderate ARDS on lung-protective ventilation. Caution should be exercised, as the removal of a CM may result in circuit disconnection or accidental extubation. Nevertheless, this intervention may improve hypercapnia and promote lung-protective ventilation., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: The use of warfarin in patients undergoing hemodialysis is associated with decreased bone mineral density and an increased incidence of bone fracture. However, no studies to date have directly estimated bone quality with bone histomorphometry in patients with bone abnormalities who are taking warfarin and undergoing hemodialysis., Patient Concerns: A 47-year-old female with Noonan syndrome presented with progressive bilateral lower extremity pain on walking, and skin sclerosis. She had been undergoing maintenance hemodialysis for 25 years following 2 years of peritoneal dialysis for chronic glomerulonephritis. She had been taking warfarin as an anticoagulant agent for 13 years after she underwent an aortic valve replacement., Diagnosis: Warfarin-induced impairment of bone material quality., Interventions and Outcomes: Histomorphometric analysis of the bone biopsy specimens showed impairment in bone calcification processes, a high turnover of bone remodeling, low bone volume, and mild fibrosis. The bone abnormality could not be categorized into any type of representative bone disease classification such as osteitis fibrosa, osteomalacia, adynamic bone disease, uremic osteodystrophy, or hyperparathyroidism, but was consistent with warfarin-induced impairment of bone material quality., Conclusion: Warfarin can induce impairment of bone material quality in a patient undergoing hemodialysis.

We examined the effect of alpha(1)-adrenoceptor subtype-specific stimulation on L-type Ca2+ current (I(Ca)) and elucidated the subtype-specific intracellular mechanisms for the regulation of L-type Ca2+ channels in isolated rat ventricular myocytes. We confirmed the protein expression of alpha(1A)- and alpha(1B)-adrenoceptor subtypes at the transverse tubules (T-tubules) and found that simultaneous stimulation of these 2 receptor subtypes by nonsubtype selective agonist, phenylephrine, showed 2 opposite effects on I(Ca) (transient decrease followed by sustained increase). However, selective alpha(1A)-adrenoceptor stimulation (> or =0.1 micromol/L A61603) only potentiated I(Ca), and selective alpha(1B)-adrenoceptor stimulation (10 mumol/L phenylephrine with 2 micromol/L WB4101) only decreased I(Ca). The positive effect by alpha(1A)-adrenoceptor stimulation was blocked by the inhibition of phospholipase C (PLC), protein kinase C (PKC), or Ca2+/calmodulin-dependent protein kinase II (CaMKII). The negative effect by alpha(1B)-adrenoceptor stimulation disappeared after the treatment of pertussis toxin or by the prepulse depolarization, but was not attributable to the inhibition of cAMP-dependent pathway. The translocation of PKCdelta and epsilon to the T-tubules was observed only after alpha(1A)-adrenoceptor stimulation, but not after alpha(1B)-adrenoceptor stimulation. Immunoprecipitation analysis revealed that alpha(1A)-adrenoceptor was associated with G(q/11), but alpha(1B)-adrenoceptor interacted with one of the pertussis toxin-sensitive G proteins, G(o). These findings demonstrated that the interactions of alpha(1)-adrenoceptor subtypes with different G proteins elicit the formation of separate signaling cascades, which produce the opposite effects on I(Ca). The coupling of alpha(1A)-adrenoceptor with G(q/11)-PLC-PKC-CaMKII pathway potentiates I(Ca). In contrast, alpha(1B)-adrenoceptor interacts with G(o), of which the betagamma-complex might directly inhibit the channel activity at T-tubules.

Background: Recent evidence suggests that ropivacaine exerts markedly less cardiotoxicity compared with bupivacaine; however, the mechanisms are not fully understood at the molecular level., Methods: Isolated ferret ventricular papillary muscles were microinjected with the Ca-binding photoprotein aequorin, and intracellular Ca transients and tension were simultaneously measured during twitch in the absence and presence of bupivacaine or ropivacaine., Results: Bupivacaine and ropivacaine (10, 30, and 100 microm) reduced peak systolic [Ca]i and tension in a concentration-dependent manner. The effects were significantly greater for bupivacaine, particularly on tension (approximately twofold). The percentage reduction of tension was linearly correlated with that of [Ca]i for both anesthetics, with the slope of the relationship being approximately equal to 1.0 for ropivacaine and approximately equal to 1.3 for bupivacaine (slope difference, P < 0.05), suggesting that the cardiodepressant effect of ropivacaine results predominantly from inhibition of Ca transients, whereas bupivacaine suppresses Ca transients and the reaction beyond Ca transients, i.e., myofibrillar activation, as well. BAY K 8644, a Ca channel opener, abolished the inhibitory effects of ropivacaine on Ca transients and tension, whereas BAY K 8644 only partially inhibited the effects of bupivacaine, particularly the effects on tension., Conclusion: The cardiodepressant effect of bupivacaine is approximately twofold greater than that of ropivacaine. Bupivacaine suppresses Ca transients more markedly than does ropivacaine and reduces myofibrillar activation, which may at least in part underlie the greater inhibitory effect of bupivacaine on cardiac contractions. These results suggest that ropivacaine has a more favorable profile as a local anesthetic in the clinical settings.

Background: Bupivacaine exhibits a cardiodepressant effect, the molecular mechanism(s) of which have yet to be fully understood. Bupivacaine may directly act on contractile proteins and thereby decrease myofibrillar Ca2+ sensitivity., Methods: Rat ventricular muscle was used. First, the effect of bupivacaine was examined on tetanic contractions in isolated intact myocytes. Next, Triton X-100-treated ventricular trabeculae were used to investigate the effect of bupivacaine on the pCa (= -log [Ca2+ ])-tension relation as well as on maximal Ca2+ -activated tension. Furthermore, to test whether bupivacaine inhibits the pathway downstream from Ca2+ binding to troponin C, tension was elicited in the skinned preparations by lowering the Mg-adenosine triphosphate (MgATP) concentration in the absence of Ca2+. The effect of bupivacaine on the pMgATP (= -log [MgATP])-tension relation was examined., Results: In myocytes, 3 microm bupivacaine significantly (P < 0.01) increased intracellular Ca2+ concentration required for 5% cell shortening from the resting cell length. In skinned preparations, bupivacaine shifted the pCa-tension relation to the lower pCa side; the midpoint of the pCa curve (pCa50) was significantly (P < 0.05) changed by 10 and 100 microm bupivacaine. A highly correlated linear relation (R = 0.81; P< 0.0005) was present between pCa50 and maximal Ca2+ -activated tension. Bupivacaine (10 and 100 microm) significantly (P < 0.05) shifted the midpoint of the pMgATP-tension relation to the higher pMgATP side., Conclusions: Bupivacaine decreases myofibrillar Ca2+ sensitivity in ventricular muscle, and this is coupled with the compound's inhibitory effect on the pathway beyond Ca2+ binding to troponin C, possibly on the actomyosin interaction. The current results may partly explain the overall cardiodepressant effect of bupivacaine in vivo.

Background: At the basis of the Frank-Starling mechanism is the intrinsic ability of cardiac muscle to produce active tension in response to stretch. Titin, a giant filamentous molecule involved in passive tension development, is intimately associated with the thick filament in the sarcomere. Titin may therefore contribute to active tension development by modulating the thick filament structure when the muscle is elongated., Methods and Results: Rat skinned right ventricular trabeculae were used. Passive tension at a sarcomere length (SL) of 2.0 to 2.4 micrometer was decreased after treatment of the preparation with trypsin (0.25 microgram/mL) for 13 minutes in the relaxed state at 20 degrees C. This mild trypsin treatment degraded titin without affecting other major contractile proteins. The sarcomere structure was little affected by brief contractions in the trypsin-treated preparations. When SL was adjusted to the slack SL (1.9 micrometer), active tension was unaffected by trypsin under partial (pCa 5.55) and maximal (pCa 4.8) activation. At longer SLs, however, active tension was significantly (P<0.01) decreased after trypsin treatment at either pCa. The increase in active tension on reduction of interfilament lattice spacing, produced by dextran T-500 (molecular weight approximately 500 000), was not influenced by trypsin (SL 1.9 micrometer). In trypsin-treated preparations, the increase in active tension as a function of muscle diameter was nearly the same for lengthening and osmotic compression at the slack SL., Conclusions: The length-dependent activation in cardiac muscle, an underlying mechanism of the Frank-Starling law of the heart, is at the myofilament level, predominantly modulated by titin and interfilament lattice spacing changes.

The effect of MgADP on the sarcomere length (SL) dependence of tension generation was investigated using skinned rat ventricular trabeculae. Increasing SL from 1.9 to 2.3 microm decreased the muscle width by approximately 11% and shifted the midpoint of the pCa-tension relationship (pCa(50)) leftward by about 0.2 pCa units. MgADP (0.1, 1, and 5 mmol/L) augmented maximal and submaximal Ca(2+)-activated tension and concomitantly diminished the SL-dependent shift of pCa(50) in a concentration-dependent manner. In contrast, pimobendan, a Ca(2+) sensitizer, which promotes Ca(2+) binding to troponin C (TnC), exhibited no effect on the SL-dependent shift of pCa(50), suggesting that TnC does not participate in the modulation of SL-dependent tension generation by MgADP. At a SL of 1. 9 microm, osmotic compression, produced by 5% wt/vol dextran (molecular weight approximately 464 000), reduced the muscle width by approximately 13% and shifted pCa(50) leftward to a similar degree as that observed when increasing SL to 2.3 microm. This favors the idea that a decrease in the interfilament lattice spacing is the primary mechanism for SL-dependent tension generation. MgADP (5 mmol/L) markedly attenuated the dextran-induced shift of pCa(50), and the degree of attenuation was similar to that observed in a study of varying SL. The actomyosin-ADP complex (AM.ADP) induced by exogenous MgADP has been reported to cooperatively promote myosin attachment to the thin filament. We hereby conclude that the increase in the number of force-generating crossbridges on a decrease in the lattice spacing is masked by the cooperative effect of AM.ADP, resulting in depressed SL-dependent tension generation.

We investigated the effects of an active metabolite of pimobendan, UD-CG 212 Cl, on Ca(2+) transients and tension using the aequorin method. When extracellular [Ca(2+)] ([Ca2+]o) in the Tyrode's solution was 2 mM, UD-CG 212 C1 (10(-7)-10(-4)M) increased the peak of Ca(2+) transients, accompanying a slight increase in peak tension. When [Ca(2+)]o was decreased to 0.5 mM, the twitch-potentiating effect of UD-CG 212 C1 was more remarkable, but the increase in the Ca(2+) transients at low concentrations of UD-CG 212 C1 (10(-7)-10(-6)M) was not significant as it was at 2 mM [Ca2+]o. The effects of UD-CG 212 Cl on the time courses of Ca(2+) transients and tension were evaluated at 0.5 mM [Ca2+]o. UD-CG 212 Cl shortened the decay time of Ca(2+) transients and the time to peak tension. However, the relaxation time was not significantly altered. UD-CG 212 C1 (10(-6)M) did not significantly change the relation between [Ca(2+)]i and tension in tetanic contraction. Therefore, the twitch-potentiating effect of UD-CG 212 Cl might not be due to an increase in the Ca(2+) sensitivity of the contractile elements. The slight increase in cyclic AMP due to the inhibition of phosphodiesterase type III by UD-CG 212 Cl could explain the twitch-potentiating effect and the faster time courses of Ca(2+) transients and tension.

We investigated the mechanisms of the effects of a newly synthesized cyclic AMP phosphodiesterase inhibitor (PDEI: 1,5-dihydro-7-(1-piperidinyl)imidazo[2,1-beta]quinazolin- 2(3H)-one dihydrochloride hydrate, DN-9693) on intracellular Ca2+ transients and tension in ferret papillary muscles. We used the aequorin method to measure Ca2+ transients in intact preparations. DN-9693 (1-100 microM) increased the peaks of both Ca2+ transients and tension. The potentiation of Ca2+ transients by DN-9693 was significant at lower concentrations (1-10 microM) but not at higher concentrations (50 and 100 microM). The peak of tension was significantly increased when the concentration of DN-9693 was increased (1-100 microM). In addition, the time to peak light was shortened at lower concentrations (1 and 5 microM). Other parameters of Ca2+ transients were not significantly altered. The time course of tension was not affected by DN-9693. In Triton X-100-treated skinned preparations, DN-9693 decreased the Ca2+ concentration required for half-maximal activation of the pCa-tension relation. These results suggest that the positive inotropic effect of DN-9693 is attributable to the alteration in Ca2+ handling of sarcoplasmic reticulum (SR) and Ca2+ sensitization of the myofilaments.

We investigated the effects of a newly synthesized dihydropyridine (DHP) derivative (NZ-105) on intracellular Ca transients and contraction in ferret ventricular muscles, using the aequorin method. Low concentrations of NZ-105 (10(-9)-10(-7) M) showed no significant effects on the light signal of aequorin and tension in twitch. High concentrations of NZ-105 (10(-6)-10(-5) M) inhibited the peaks of the light signal and tension without altering their time courses. The relation between the peaks of the light signal and tension in twitch, measured in solutions with varying Ca2+ concentrations, was shifted to the left by NZ-105. The relation between [Ca2+]i and tension measured in tetanic contraction was also shifted to the left by NZ-105. These results suggest that the inhibitory effect of NZ-105 on contraction in mammalian cardiac muscle is curtailed by an increase in Ca sensitivity of the contractile elements.

Serum levels of carcinoembryonic antigen (CEA) were measured by a radioimmunoassay technique. The mean CEA level for 80 controls was 2.03 ng/ml with a standard deviation of 0.49 ng/ml. Hence, the upper limit of normal for serum CEA levels was considered to be 3.01 ng/ml, ie, two standard deviations above the mean. Serum CEA levels were measured in 86 patients with cervical squamous cell carcinoma, Stages 0 through IV. Thirty-five of the 74 patients with invasive cervical carcinoma were CEA-positive (serum levels above normal); patients with cervical dysplasia or carcinoma in situ were all CEA-negative. Study of the distribution of these patients together with the extent of their disease leads to the following conclusions: a) determination of serum CEA levels cannot serve as a test for the early diagnosis of cervical cancer or precancerous lesions; b) in patients with clinical Stage I or II cervical cancer, an elevated serum CEA level indicates a greater likelihood of parametrial invasion or lymph node metastasis; c) in patients with treated carcinoma of the cervix, continued normal levels of serum CEA affirm continued absence of the disease, whereas development of an elevated level is highly suspicious of occult residual or recurrent cancer. The authors urge periodic determinations of serum CEA levels in patients with treated cervical cancer.

Serum ferritin levels were determined by a radioimmunoassay (a 2-site solid-phase method). The mean ferritin level for 52 control women was 35 ng/ml, and the 2nd to 98th percentile reference intervals were 3.9 to 108 ng/ml. The upper limit of ferritin level for controls was determined to be 108 ng/ml, and the sera from cervical cancer patients were screened. In 98 patients with untreated cervical cancer, 50 (51%) had elevated levels of serum ferritin. Among 36 patients who were surgically treated and whose resected specimens were pathologically examined, 12 of 16 patients (75%) with ferritin levels above normal and 3 of 20 patients (15%) with levels below 108 ng/ml had parametrial invasion and/or lymph node metastasis. Serum ferritin levels were measured at 2- to 4-week intervals and 6 months after treatment on 21 patients with levels elevated before therapy. Ferritin levels decreased to the normal range 4 weeks after treatment in many patients, but the development of elevated levels thereafter was closely associated with a poor prognosis. Measurement of serum ferritin may be useful in predicting the extent of cancer beyond the cervix and the prognosis for cervical cancer patients.

Coenzyme Q10 (CoQ10) is an essential component of the mitochondrial membrane and plays an important role in the maintenance of normal cardiac function. To evaluate the effects of ocular timolol on the cardiovascular system and determine the protective effect of CoQ10, 16 patients with glaucoma were studied using impedance cardiography. Following instillation of 1 mg timolol maleate in each eye, heart rate (HR) and stroke index (SI) decreased, and total peripheral resistance index (TPRI) increased significantly. Reexamination was performed after 6 weeks of 90 mg oral CoQ10. Despite decreases in HR, percent changes in HR were significantly less after CoQ10 at 120 min. Stroke index showed an initial increase which was not observed without CoQ10. These data suggest that CoQ10 delayed the appearance of inotropic blockade of timolol and hastened the disappearance of chronotropic blockade. Additional study of six normal volunteers with 6 weeks of oral CoQ10 showed a similar decrease of intraocular pressure after timolol instillation as compared to those without CoQ10. Thus, administration of oral CoQ10 in patients receiving ocular timolol may be useful in mitigating cardiovascular side effects without affecting intraocular pressure in the treatment of glaucoma.