Oocyte activation with phospholipase Cζ mRNA induces repetitive intracellular Ca2+ rises and improves the quality of pig embryos after intracytoplasmic sperm injection.

For the intracytoplasmic sperm injection (ICSI) procedure in pigs, an electrical pulse (EP) has been used as an effective method for oocyte stimulation, but unlike sperm, EP is unable to induce Ca2+ oscillations. In this study, we investigated the effects of generating artificial Ca2+ oscillations with phospholipase Cζ (PLCζ) mRNA, a candidate sperm factor, on fertilization, embryonic development, and gene expression after ICSI. Firstly, the concentration of PLCζ mRNA of a fixed volume (1.0 pl) that would induce a pattern of Ca2+ rise similar to that of in vitro fertilized (IVF) sperm was examined and determined to be 300 ng/µl. Secondly, the effects of oocyte stimulation methods on fertilization and embryonic development were investigated. ICSI-oocytes were activated by EP (EP group) or by PLCζ mRNA (PLCζ group). Furthermore, IVF-oocytes (IVF group) and ICSI-oocytes with and without an injection of buffer (buffer and untreated groups, respectively) were used as controls. It was found that the rates of normal fertilization in the PLCζ and EP groups were significantly higher than those in the buffer and untreated groups. The blastocyst formation rates did not differ among the groups. The embryo quality in the EP group was inferior to those in the PLCζ and IVF groups. Additionally, the expression level of a proapoptosis-related gene (Caspase-3) in the EP group was significantly higher than those in the PLCζ and IVF groups. Our data suggest that oocyte activation by PLCζ mRNA has the effect of improving embryo quality.

Continuous cyclosporine a infusion in patients with severe Kawasaki disease.

BACKGROUND: The efficacy and safety of continuous intravenous infusion of cyclosporine A (CICsA) in patients with intravenous immunoglobulin-resistant Kawasaki disease are unclear. METHODS: Between 2010 and 2020, 83 patients with Kawasaki disease that was not responsive to intravenous immunoglobulin (total dose ≥ 4 g/kg) were enrolled. All patients were started on CICsA (3 mg/kg/day) and switched to oral cyclosporine A (CsA) (4-6 mg/kg/day). Treatment efficacy, occurrence of coronary artery lesions (CALs), and laboratory parameters were evaluated. Patients were divided into two groups according to CICsA response: the responder group (afebrile ≤24 h after CICsA without additional treatment) and the weak responder group (afebrile >24 h after CICsA requiring additional treatment). RESULTS: Fifty-five patients became afebrile within 24 and 74 h became afebrile in less than 72 h. Adverse events included hypertension in four and hyperkalemia in two patients. Thirty-nine patients were defined as responders and 44 patients as weak responders. There were no significant differences in CAL between the two groups. In weak responders, white blood cells, neutrophils, and C-reactive protein levels were higher, and albumin, immunoglobulin G, and CsA concentration were lower than in responders, indicating that weak responders had more severe inflammatory findings. However, there were no significant differences in CAL. Logistic regression analysis revealed that the response to treatment for CICsA was associated with immunoglobulin G levels at baseline and CsA concentrations the day after CICsA. CONCLUSION: Although CICsA required additional treatments in about half of the cases, a favorable clinical course was observed by using this strategy, especially for reducing CAL.

Rapid and Systematic Exploration of Chemical Space Relevant to Artemisinins: Anti-malarial Activities of Skeletally Diversified Tetracyclic Peroxides and 6-Aza-artemisinins.

To achieve both structural changes and rapid synthesis of the tetracyclic scaffold relevant to artemisinins, we explored two kinds of de novo synthetic approaches that generate both skeletally diversified tetracyclic peroxides and 6-aza-artemisinins. The anti-malarial activities of the tetracyclic peroxides with distinct skeletal arrays, however, were moderate and far inferior to artemisinins. Given the privileged scaffold of artemisinins, we next envisioned element implantation at the C6 position with a nitrogen without the trimmings of substituents and functional groups. This molecular design allowed the deep-seated structural modification of the hitherto unexplored cyclohexane moiety (C-ring) while keeping the three-dimensional structure of artemisinins. Notably, this approach induced dramatic changes of retrosynthetic transforms that allow an expeditious catalytic asymmetric synthesis with generation of substitutional variations at three sites (N6, C9, and C3) of the 6-aza-artemisinins. These de novo synthetic approaches led to the lead discovery with substantial intensification of the in vivo activities, which undermine the prevailing notion that the C-ring of artemisinins appears to be merely a structural unit but to be a functional area as the anti-malarial pharmacophore. Furthermore, we unexpectedly found that racemic 6-aza-artemisinin (33) exerted exceedingly potent in vivo efficacies superior to the chiral one and the first-line drug, artesunate.

Clinical and Morphological Outcomes in Endovascular Aortic Repair of Abdominal Aortic Aneurysm Using GORE C3 EXCLUDER: Comparison between Patients Treated within and Outside Instructions for Use.

BACKGROUND: The goals of this study were to evaluate mid-term outcome in endovascular aortic repair (EVAR) of abdominal aortic aneurysm (AAA) using a GORE C3 EXCLUDER and compare results between patients treated within and outside the instructions for use (IFU). METHODS: Over a 3-year period spanning October 2013 to September 2016, consecutive patients undergoing EVAR for AAA using the C3 EXCLUDER at Tokyo Medical University Hospital were registered on a prospectively maintained database. The data thus obtained were retrospectively analyzed. RESULTS: A total of 109 AAA patients underwent EVAR using the C3 EXCLUDER. The median follow-up duration was 729 days (interquartile range, 542-1,069 days). Technical success was achieved in 98.2% of cases. Adjunctive, unplanned proximal cuff-extender implantation was required in 8 patients (9.2%). Of the total number, 29 (24.8%) were categorized as being treated outside the IFU. No significant difference was observed in freedom from overall mortality or aneurysm-related mortality between patients treated within and outside the IFU. Freedom from reintervention tended to be lower in patients treated outside the IFU. There was aneurysm sac shrinkage (≥5 mm) in 30.3% and 39.1%; stable aneurysm sac in 69.7% and 56.3%; and aneurysm sac expansion (≥5 mm) in 0% and 4.7% of cases at 1 and 2 years, respectively. No significant difference was observed in aneurysm sac shrinkage between patients treated within and outside the IFU. CONCLUSIONS: The C3 EXCLUDER showed good clinical performance and aneurysm sac shrinkage, regardless of whether the patient was treated within or outside the IFU. The results suggest, however, that in those treated outside the IFU, precise planning, careful operative procedure, and subsequent follow-up are required to obtain short-term and mid- to long-term success in EVAR for AAA using the C3 EXCLUDER.

Extracorporeal membrane oxygenation after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.

BACKGROUND: Pulmonary endarterectomy (PEA) is the treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH) but can result in respiratory and cardiac complications that may require extracorporeal membrane oxygenation (ECMO). We reviewed our experience with ECMO in patients undergoing PEA. METHODS AND RESULTS: Between January 2012 and August 2015, 35 patients underwent PEA for CTEPH. In all, four patients (11%) required veno-arterial (V-A) ECMO support due to severe cardiac and respiratory failure, including severe reperfusion pulmonary edema and persistent pulmonary hypertension. No significant differences in preoperative characteristics were found between patients who required ECMO and those who did not require ECMO. ECMO support was associated with a significantly higher incidence of postoperative respiratory complications, a longer intensive care unit stay, increased in-hospital mortality, residual pulmonary hypertension, and postoperative balloon pulmonary angioplasty (BPA). The postoperative mean pulmonary artery pressure and pulmonary vascular resistance were significantly higher in patients requiring ECMO. All patients requiring ECMO were successfully weaned off ECMO support (100%), and three of them were discharged from the hospital alive (75%). CONCLUSIONS: Patients with CTEPH may benefit from ECMO after PEA for cardiac and respiratory complications. A prompt decision to use V-A ECMO is critical for a successful outcome in these patients.

Ganglioside GM3 is essential for the structural integrity and function of cochlear hair cells.

GM3 synthase (ST3GAL5) is the first biosynthetic enzyme of a- and b-series gangliosides. Patients with GM3 synthase deficiency suffer severe neurological disability and deafness. Eight children (ages 4.1 ± 2.3 years) homozygous for ST3GAL5 c.694C>T had no detectable GM3 (a-series) or GD3 (b-series) in plasma. Their auditory function was characterized by the absence of middle ear muscle reflexes, distortion product otoacoustic emissions and cochlear microphonics, as well as abnormal auditory brainstem responses and cortical auditory-evoked potentials. In St3gal5(-/-) mice, stereocilia of outer hair cells showed signs of degeneration as early as postnatal Day 3 (P3); thereafter, blebs devoid of actin or tubulin appeared at the region of vestigial kinocilia, suggesting impaired vesicular trafficking. Stereocilia of St3gal5(-/-) inner hair cells were fused by P17, and protein tyrosine phosphatase receptor Q, normally linked to myosin VI at the tapered base of stereocilia, was maldistributed along the cell membrane. B4galnt1(-/-) (GM2 synthase-deficient) mice expressing only GM3 and GD3 gangliosides had normal auditory structure and function. Thus, GM3-dependent membrane microdomains might be essential for the proper organization and maintenance of stereocilia in auditory hair cells.

Purification and characterization of enantioselective N-acetyl-ß-Phe acylases from Burkholderia sp. AJ110349.

For the production of enantiopure ß-amino acids, enantioselective resolution of N-acyl ß-amino acids using acylases, especially those recognizing N-acetyl-ß-amino acids, is one of the most attractive methods. Burkholderia sp. AJ110349 had been reported to exhibit either (R)- or (S)-enantiomer selective N-acetyl-ß-Phe amidohydrolyzing activity, and in this study, both (R)- and (S)-enantioselective N-acetyl-ß-Phe acylases were purified to be electrophoretically pure and determined the sequences, respectively. They were quite different in terms of enantioselectivities and in their amino acids sequences and molecular weights. Although both the purified acylases were confirmed to catalyze N-acetyl hydrolyzing activities, neither of them show sequence similarities to the N-acetyl-α-amino acid acylases reported thus far. Both (R)- and (S)-enantioselective N-acetyl-ß-Phe acylase were expressed in Escherichia coli. Using these recombinant strains, enantiomerically pure (R)-ß-Phe (>99% ee) and (S)-ß-Phe (>99% ee) were obtained from the racemic substrate.

Efficient pig ICSI using Percoll-selected spermatozoa; evidence for the essential role of phospholipase C-ζ in ICSI success.

In pigs, the damaged sperm membrane leads to leakage of phospholipase C-ζ (PLCζ), which has been identified as a sperm factor, and a reduction of oocyte-activating ability. In this study, we investigated whether sperm selected by Percoll gradient centrifugation (Percoll) have sufficient PLCζ, and whether the efficiency of fertilization and blastocyst formation after intracytoplasmic sperm injection (ICSI) using Percoll-selected sperm can be improved. Percoll-selected sperm (Percoll group) or sperm without Percoll selection (Control group) were used. A proportion of the oocytes injected with control sperm were subjected to electrical stimulation at 1 h after ICSI (Cont + ES group). It was found that the Percoll group showed a large amount of PLCζ in comparison with the Control group. Furthermore, application of Percoll-selected sperm for ICSI increased the efficiency of fertilization and embryo development. Thus, these results indicate the Percoll-selected sperm have sufficient PLCζ and high oocyte-activating ability after ICSI in pigs.

Lack of calcium oscillation causes failure of oocyte activation after intracytoplasmic sperm injection in pigs.

In pigs, the efficiency of embryo production after intracytoplasmic sperm injection (ICSI) is still low because of frequent failure of normal fertilization, which involves formation of two polar bodies and two pronuclei. To clarify the reasons for this, we hypothesized that ICSI does not properly trigger sperm-induced fertilization events, especially intracellular Ca2+ signaling, also known as Ca2+ oscillation. We also suspected that the use of in vitro-matured oocytes might negatively affect fertilization events and embryonic development of sperm-injected oocytes. Therefore, we compared the patterns of Ca2+ oscillation, the efficiency of oocyte activation and normal fertilization, and embryo development to the blastocyst stage among in vivo- or in vitro-matured oocytes after ICSI or in vitro fertilization (IVF). Unexpectedly, we found that the pattern of Ca2+ oscillation, such as the frequency and amplitude of Ca2+ rises, in oocytes after ICSI was similar to that in oocytes after IVF, irrespective of the oocyte source. However, half of the oocytes failed to become activated after ICSI and showed no Ca2+ oscillation. Moreover, the embryonic development of normal fertilized oocytes was reduced when in vitro-matured oocytes were used, irrespective of the fertilization method employed. These findings suggest that low embryo production efficiency after ICSI is attributable mainly to poor developmental ability of in vitro-matured oocytes and a lack of Ca2+ oscillation, rather than the pattern of oscillation.

The Role of Common Femoral Artery Endarterectomy in the Endovascular Era.

BACKGROUND: The purpose of this study was to review our experiences treating peripheral artery disease (PAD) by common femoral artery endarterectomy (CFE) with and without endovascular therapy (EVT), and to describe the role of CFE in the endovascular era. METHODS: We retrospectively reviewed a contemporary series of 38 limbs from January 2010 to September 2014. Clinical outcomes of primary patency, assisted primary patency, limb salvage, and survival were analyzed with the Kaplan-Meier method. Multivariable perioperative predictors of primary patency were identified using the stepwise Cox proportional hazards regression model. RESULTS: Hemodynamic success was achieved in 36 of the 38 limbs (95%). The mean ankle brachial pressure index improved significantly, rising from 0.56 ± 0.04 preoperatively to 0.89 ± 0.04 postoperatively (P = 0.0001). Overall primary and assisted primary patency rates, respectively, were 90% and 100% at 12 months and 85% and 94% at 24 months. There was no significant difference in primary patency rate between isolated CFE and hybrid CFE plus EVT. Both limb salvage and survival rates were 97% at 12 months and 97% at 24 months. Multivariate Cox regression analysis revealed that no clinical or perioperative risk factors were predictive of decreased primary patency. CONCLUSIONS: CFE is a safe, effective, and durable procedure for common femoral artery disease, and hybrid CFE plus EVT can be a valid alternative to open surgical bypass for multilevel occlusive artery disease. These observations stress that CFE plays a vital role in the management of PAD even in the endovascular era.

Weight loss may be a better approach for managing musculoskeletal conditions than increasing muscle mass and strength.

To prevent or remedy musculoskeletal conditions, the relationship between obesity and the characteristics of muscle mass and strength need to be clarified. [Subjects and Methods] A total of 259 Japanese males aged 30-64 years were classified into 4 groups according to the Japanese obesity criteria. Body composition was evaluated, and handgrip strength and knee extensor strength were measured for the upper and lower extremities, respectively. Physical performance was evaluated with a jump test. [Results] Obesity was positively correlated with skeletal muscle mass index, percentage of whole-body fat, and leg muscle strength and negatively correlated with the percentage of muscle mass index, body weight-normalized handgrip strength, and knee extensor strength, and the jump test results. [Conclusion] Weight loss may be a better approach than increasing muscle mass and strength to improve musculoskeletal conditions in obese adult males.

Local Area Tactile Stimulation Using Interference of Multi-Frequency Airborne Ultrasound.

In spatiotemporal modulation (STM) and lateral modulation (LM) used in conventional mid-air ultrasound tactile stimulation, single or multiple focuses are moved by switching the ultrasound transducer phases. A problem with the phase switching method is the limitation of the focus motion speed due to rapid phase switching that causes sound pressure fluctuations. This paper proposes an LM method using multiple-frequency ultrasound to shift the ultrasound focal point without switching the phase. This method can demonstrate a continuous and stable moving stimulus with high-frequency components, without producing unnecessary audible noise. Using the proposed broadband LM covering up to 400 Hz, we found that a high-frequency 400 Hz LM applied at a finger pad can display a stimulation area with the diameters comparable to or less than the half wavelength of 40 kHz ultrasound, where the perceptual size was evaluated as 4. 2 mm for the long axis diameter and 3. 4 mm for the short axis diameter.

Is Common Trunk Anomaly Frequent in Hemifacial Spasm? Comparison with Normal Subjects Using Magnetic Resonance Imaging.

OBJECTIVE: Hemifacial spasm (HFS) results from vascular compression at the root exit of the facial nerve. Although the underlying etiology has yet to be identified, it has been suggested that congenital vascular anomalies are involved. We have hypothesized common trunk anomaly of the anterior inferior cerebellar artery (AICA) and posterior inferior cerebellar artery (PICA) which may play a role in HFS. However, no previous studies have directly compared the incidence of this anomaly between HFS patients and normal subjects. The present study was designed to address this gap in the literature. METHODS: This case-control study compared magnetic resonance angiography data from 65 HFS patients and 65 normal subjects. Dominant AICA/PICA is defined as the absence of PICA/AICA, with the remaining AICA/PICA supplying both vascular territories. The term "common trunk" encompasses both dominant AICA and dominant PICA. The frequency of common trunk and dominant AICA/PICA was compared between the 2 groups. RESULTS: There were no significant differences in the incidence of a common trunk (68.5% and 64.6%), dominant AICA (30.8% and 32.3%) and dominant PICA (37.7% and 32.3%) between the 2 groups. Additionally, no differences were found in the frequency of atherosclerosis risk factors. CONCLUSIONS: There was no apparent association between common trunk anomaly and HFS. It is suspected that some vascular anomalies other than a common trunk are involved in HFS.

A technique for reconstruction of a giant extracranial internal carotid artery aneurysm: A technical note.

Background: Surgery is effective for extracranial internal carotid artery (EICA) aneurysms. However, the risk of cranial nerve injury associated with surgical repair, such as graft-assisted resection and extracranial-intracranial bypass techniques, is relatively high. Here, we report two cases of surgical treatment for EICA aneurysms and describe the surgical techniques and strategies to avoid cranial nerve injury. Methods: Two patients presented to our facility with an increasing cervical pulsatile mass and no neurological symptoms. Angiography showed a large aneurysm in the cervical internal carotid artery. Surgical treatment was performed to prevent rupture of the aneurysm. In both patients, the aneurysm was strongly attached to the vagus nerve. The aneurysm and vagus nerve were carefully dissected using a low-power bipolar (20 Malis; 3 watts), leaving connective tissue on the vagus nerve side. Results: The aneurysm was detached from the vagus nerve without injury. Based on intraoperative findings, one patient underwent clipping, and the other underwent aneurysmectomy and primary closure for aneurysm obliteration and angioplasty. Both patients were discharged without any cranial nerve dysfunction. Conclusion: The selection of a strategy based on intraoperative findings and low-power bipolar cutting is important for the treatment of extracranial carotid artery aneurysms to preserve cranial nerves.

Sound Pressure Field Reconstruction for Airborne Ultrasound Tactile Display Encountering Obstacles.

Airborne ultrasound tactile display (AUTD) is used to provide non-contact tactile sensations with specific foci sound fields through the optimization of transducer phases. However, most existing optimization approaches are not directly applicable in case of an inhomogeneous medium, such as in the presence of obstacles between the AUTD and objective sound field. Certain methods can perform optimizations by considering the sound-scattering surfaces of the obstacles to compute the transmission matrix, which requires several complex measurements. This study proposed two methods to reconstruct the sound field under an inhomogeneous medium, wherein the need to calculate the impact of the obstacles was eliminated. The two methods are Bayesian optimization and greedy algorithm with brute-force search. Further, the process of the foci field generation was assumed as a black box. The proposed methods require only the pressure intensity at the control point generated by the input phases, discarding the need for transmission matrix in the presence of obstacles. Moreover, these methods offer the advantage of optimization of the phases in the presence of obstacles. This study explains the working of proposed methods in different forms of foci fields encountering obstacles.

Balloon pulmonary angioplasty followed by pulmonary endarterectomy: Combination treatment for high-surgical-risk patients with chronic thromboembolic pulmonary hypertension.

OBJECTIVES: Our goal was to evaluate the combined effects of balloon pulmonary angioplasty (BPA) followed by pulmonary endarterectomy (PEA) to treat high-surgical-risk patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: This study included 58 patients with CTEPH who had pulmonary vascular resistance of ≥1000 dyn·s/cm5, mean pulmonary arterial pressure (mPAP) of ≥45 mmHg or mPAP of 38-44 mmHg with comorbidities. Of these, 21 patients underwent the combined therapy of BPA followed by PEA (BPA group) and 37 underwent direct PEA (non-BPA group). Preoperative and postoperative results were compared between the 2 groups. An early postoperative composite event comprised the postoperative use of extracorporeal membrane oxygenation or intra-aortic balloon pump, in-hospital death, rescue BPA, prolonged ventilation, tracheostomy, prolonged stay in the intensive care unit, deep sternal wound infection and cerebral infarction. RESULTS: Before the first intervention (before BPA or direct PEA), patients in the BPA group had a higher mPAP than those in the non-BPA group. After undergoing BPA before PEA, the BPA group demonstrated significantly decreased mPAP and pulmonary vascular resistance (43 vs 52 mmHg, P < 0.001; 636 vs 965 dyn·s/cm5, P = 0.003, respectively) and significantly increased cardiac output (4.1 vs 3.5 l/min, P = 0.041). Notably, the number of patients with the early postoperative composite event was significantly lower in the BPA group than in the non-BPA group (4.8% vs 35.1%, P = 0.011). CONCLUSIONS: Compared with direct PEA, the combination therapy of BPA followed by PEA can be a feasible and effective risk-reduction strategy for high-surgical-risk patients with CTEPH.

Impact of the omicron phase on a highly advanced medical facility in Japan.

Background: Eight waves of the coronavirus disease 2019 (COVID-19) epidemic have been observed in Japan. This retrospective study was conducted to clarify the clinical characteristics of pediatric COVID-19 patients. Methods: We studied 121 patients admitted to the Jichi Children's Medical Center Tochigi between April 2020 and March 2023. Incidence of pediatric COVID-19 in Tochigi Prefecture was used to examine hospitalization and severe illness rates. Results: The mean age of the patients was 3 years and 8 months. One hundred and eleven patients (91.7%) were hospitalized after January 2022 (after the 6th wave), when the Omicron strain became endemic in Japan. Convulsions occurred in 30 patients (24.8%), all of whom were admitted after the 6th wave. Twenty-three of the 30 patients had no underlying disease. Eleven patients (9.1%) were diagnosed with acute encephalopathy. One patient died due to hemorrhagic shock and encephalopathy syndrome and two had sequelae after the 6th wave. The patient who died due to encephalopathy had hypercytokinemia. In the Tochigi Prefecture, the number of pediatric COVID-19 patients increased after the 6th wave, but the hospitalization rate declined. The rate of severe illness did not change before the end of 5th and after the 6th wave. Conclusion: Although the rate of severe illness in patients with pediatric COVID-19 did not increase after the 6th wave, some patients had complicated critical illnesses. Systemic inflammatory reaction was considered to have been associated with the severe encephalopathy.

Predictors of procedural complications in balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension.

BACKGROUND: Balloon pulmonary angioplasty (BPA) is an effective treatment for inoperable chronic thromboembolic pulmonary hypertension, with good results reported for residual pulmonary hypertension (PH) after pulmonary endarterectomy (PEA). However, BPA is associated with complications, such as pulmonary artery perforation and vascular injury, which can lead to critical pulmonary hemorrhage requiring embolization and mechanical ventilation. Furthermore, the risk factors for occurrence of complications in BPA are unclear; therefore, this study aimed to evaluate predictors of procedural complications in BPA. METHODS: In this retrospective study, we collected clinical data (patient characteristics, details of medical therapy, hemodynamic parameters, and details of the BPA procedure) from 321 consecutive sessions involving 81 patients who underwent BPA. Procedural complications were evaluated as endpoints. RESULTS: BPA for residual PH after PEA was performed in 141 sessions (43.9 %), which involved 37 patients. Procedural complications were observed in 79 sessions (24.6 %), including severe pulmonary hemorrhage requiring embolization in 29 sessions (9.0 % of all sessions). No patients experienced severe complications requiring intubation with mechanical ventilation or extracorporeal membrane oxygenation. Age ≥ 75 years and mean pulmonary artery pressure ≥ 30 mmHg were independent predictors of procedural complications. Residual PH after PEA was a significant predictor of severe pulmonary hemorrhage requiring embolization (adjusted odds ratio, 3.048; 95 % confidence interval, 1.042-8.914, p = 0.042). CONCLUSIONS: Older age, high pulmonary artery pressure, and residual PH after PEA increase the risk of severe pulmonary hemorrhage requiring embolization in BPA.

Mice lacking ganglioside GM3 synthase exhibit complete hearing loss due to selective degeneration of the organ of Corti.

The ganglioside GM3 synthase (SAT-I), encoded by a single-copy gene, is a primary glycosyltransferase for the synthesis of complex gangliosides. In SAT-I null mice, hearing ability, assessed by brainstem auditory-evoked potentials (BAEP), was impaired at the onset of hearing and had been completely lost by 17 days after birth (P17), showing a deformity in hair cells in the organ of Corti. By 2 months of age, the organ of Corti had selectively and completely disappeared without effect on balance or motor function or in the histology of vestibule. Interestingly, spatiotemporal changes in localization of individual gangliosides, including GM3 and GT1b, were observed during the postnatal development and maturation of the normal inner ear. GM3 expressed in almost all regions of cochlea at P3, but at the onset of hearing it distinctly localized in stria vascularis, spiral ganglion, and the organ of Corti. In addition, SAT-I null mice maintain the function of stria vascularis, because normal potassium concentration and endocochlear potential of endolymph were observed even when they lost the BAEP completely. Thus, the defect of hearing ability of SAT-I null mice could be attributed to the functional disorganization of the organ of Corti, and the expression of gangliosides, especially GM3, during the early part of the functional maturation of the cochlea could be essential for the acquisition and maintenance of hearing function.