Ryusuke Hori

Novel therapy for hearing loss: delivery of insulin-like growth factor 1 to the cochlea using gelatin hydrogel.

Hypothesis: Local application of recombinant human insulin-like growth factor 1 (rhIGF-1) via a biodegradable hydrogel after onset of noise-induced hearing loss (NIHL) can attenuate functional and histologic damage. Background: The biodegradable gelatin hydrogel makes a complex with drugs by static electric charges and releases drugs by degradation of gelatin polymers. We previously demonstrated the efficacy of local rhIGF-1 application via hydrogels before noise exposure for prevention of NIHL. Methods: First, we used an enzyme-linked immunosorbent assay to measure human IGF-1 concentrations in the cochlear fluid after placing a hydrogel containing rhIGF-1 onto the round window membrane of guinea pigs. Second, the functionality and the histology of guinea pig cochleae treated with local rhIGF-1 application at different concentrations after noise exposure were examined. Control animals were treated with a hydrogel immersed in physiologic saline alone. Results: The results revealed sustained delivery of rhIGF-1 into the cochlear fluid via the hydrogel. The measurement of auditory brainstem responses demonstrated that local rhIGF-1 treatment significantly reduced the threshold elevation from noise. Histologic analysis exhibited increased survival of outer hair cells by local rhIGF-1 application through the hydrogel. Conclusion: These findings indicate that local rhIGF-1 treatment via gelatin hydrogels is effective for treatment of NIHL.

Pharmacological inhibition of Notch signaling in the mature guinea pig cochlea

Recent studies using explant cultures have demonstrated that pharmacological inhibition of Notch signaling by &ggr;-secretase inhibitors generates supernumerary hair cells in embryonic or neonatal cochleae. The aim of this study was to examine the effects of such pharmacological inhibition on mature auditory epithelia in vivo. Normal adult guinea pig auditory epithelia exhibited weak or no immunoreactivity for Notch1 and Jagged1, whereas ototoxic treatment caused the upregulation of these molecules in damaged auditory epithelia. Local application of a &ggr;-secretase inhibitor in damaged cochleae generated ectopic hair cells in mature auditory epithelia. These findings indicate that pharmacological inhibition of Notch signaling is a possible strategy for hair cell regeneration in adult auditory epithelia.

Prostaglandin E receptor subtype EP4 agonist protects cochleae against noise-induced trauma

Prostaglandin E(1) is frequently used for the clinical treatment of acute sensorineural hearing loss. However, the mechanisms underlying the effects of prostaglandin E(1) on the inner ear have not yet been elucidated. The physiological effects of prostaglandin E(1) are mediated by the prostanoid receptors prostaglandin I receptor and the prostaglandin E receptor subtypes EP1, EP2, EP3, and EP4, the respective agonists for which have been purified. In the current study, we examined the efficacy of a local EP4 agonist application for the treatment of sensorineural hearing loss. We examined EP4 expression in the mouse cochlea using the reverse transcription-polymerase chain reaction and immunohistochemistry. The protective effects of local EP4 agonist treatment before or after noise exposure were tested in guinea pigs using measurements of auditory brain-stem responses and histological analysis. The results demonstrated EP4 expression in the cochlea, and showed that pre- and post-treatment with an EP4 agonist significantly attenuated threshold shifts of auditory brain stem responses, and significant attenuation in the loss of outer hair cells was found in local EP4 agonist treatment before noise exposure. These findings indicate that EP4 is involved in mechanisms for prostaglandin E(1) actions on the cochlea, and local EP4 agonist treatment could attenuate acute sensorineural hearing loss.

Role of prostaglandin E receptor subtypes EP2 and EP4 in autocrine and paracrine functions of vascular endothelial growth factor in the inner ear

BackgroundThe physiological effects of prostaglandin E1 (PGE1) and prostaglandin E2 (PGE2) are mediated by the prostaglandin E receptor subtypes EP1, EP2, EP3, and EP4, and the respective agonists have been purified. PGE1 and PGE2 can increase the production of vascular endothelial growth factor (VEGF), particularly through EP2 and EP4. The biological effects of VEGF are mediated by the phosphotyrosine kinase receptors fms-related tyrosine kinase-1 (Flt-1) and fetal liver kinase-1 (Flk-1). Here we examined the effects of EP2 and EP4 agonists on the production of VEGF proteins and VEGF messenger RNAs (mRNAs) in the inner ear, using an enzyme-linked immunosorbent assay and the real-time quantitative reverse transcription-polymerase chain reaction, respectively. We also examined the localization of EP2, VEGF, Flt-1, and Flk-1 in the cochlea by immunohistochemistry.ResultsThe expression of EP2 occurred in the cochlea, and the local application of an EP2 or EP4 agonist increased VEGF protein and VEGF mRNA levels in the inner ear. Furthermore, the intensity of the VEGF immunoreactivity in the spiral ganglion appeared to be increased by the local EP2 or EP4 agonist treatment. Immunoreactivity for Flt-1, and Flk-1 was found in the cochlear sensory epithelium, spiral ganglion, spiral ligament, and stria vascularis.ConclusionsThese findings demonstrate that EP2 and EP4 agonists stimulate VEGF production in the inner ear, particularly in the spiral ganglions. Moreover, the Flt-1 and Flk-1 expression observed in the present study suggests that VEGF has autocrine and paracrine actions in the cochlea. Thus, EP2 and EP4 might be involved in the mechanisms underlying the therapeutic effects of PGE1 on acute sensorineural hearing loss via VEGF production.

Prostaglandin E receptor subtype EP4 agonist serves better to protect cochlea than prostaglandin E1

OBJECTIVE The present study aimed to examine whether an E-prostanoid receptor 4 (EP4) agonist has superior protective effects to those of prostaglandin E1 (PGE1) in a guinea pig model of noise trauma. METHODS Drugs were locally applied on the round window membrane of guinea pig cochleae, followed by exposure of the test animals to intense noise. Protective effects mediated by an EP4 agonist were compared with those mediated by PGE1. Auditory function was monitored by measurements of the auditory brainstem response (ABR), and histological damage was assessed by immunohistochemical analysis of cochlear specimens. RESULTS Animals treated with an EP4 agonist exhibited significantly better hearing recovery than those pretreated with PGE1. Histologically, the numbers of remaining outer hair cells in cochleae treated with the EP4 agonist were significantly higher than in those treated with PGE1. CONCLUSION The selective activation of EP4 has a stronger protective effect on cochleae against noise trauma than does the broad activation of EPs by PGE1.

Application of a Novel Vibrating Device for Fine-Needle Aspiration Cytology

Objective: Fine-needle aspiration cytology (FNAC) is a valuable diagnostic technique. However, the procedure involves backand-forth motions of a needle within a mass, which can lead to unexpected complications. We have developed a novel device and sampling techniques that use vibration and rotation instead of backand-forth motions. Methods: The new device consists of a vibrating motor fixed to the stopper of a 5 ml syringe with its piston. A 22-gauge needle attached to the 5 ml syringe is used for FNAC. Samples were obtained from resected specimens using the following four procedures: suction only; suction and vibration for 5 seconds; suction and 180° rotation of the syringe; and suction, vibration for 5 seconds, and 180° rotation of the syringe. Samples were also obtained using the conventional technique. The numbers of well-visualized follicular groups on glass slides were counted to compare the amounts of cellular material obtained using the five different procedures. Next, 415 patients with thyroid nodules underwent ultrasound-guided FNAC to evaluate the rate of inadequacy. Results: Sufficient amounts of material were obtained from resected specimens using suction, vibration and rotation, and using the conventional technique. Inadequate thyroid FNAC material was obtained in 12.3% of cases. Conclusions: The new device and sampling techniques for thyroid FNAC collected sufficient amounts of adequate material and allowed safe and precise control of the device. Our device and sampling techniques are expected to be widely used not only for thyroid FNAC sampling but also for sampling from other anatomical sites.

Thyroid lobectomy with minimal incision approach

Thyroid surgery includes all basic head and neck surgical techniques, such as scalpel incision, skin flap elevation, layer-by-layer ablation, blood vessel and nerve management, tumor removal, and skin closure. While tumor removal without complications is a matter of course, based on the surgeon’s level of expertise, there may be differences in ablation area, incision length, operation time, amount of blood loss, etc. This study reports on thyroid lobectomy with a minimal incision approach. The minimum incision was 2 cm in length and depended on the tumor and thyroid size. The operation techniques and instruments were essentially the same as those of open thyroid surgery. The field of vision and handling space were so small that operation time and blood loss increased. A small incision has the potential advantages of good aesthetic appearance, less tissue trauma, and reduced postoperative pain. It is important that surgeons endeavor to treat patients with a minimally invasive approach.

Two Pediatric Cases of Facial Palsy Caused by Intracranial Disease

We report two pediatric cases of facial palsy caused by intracranial disease, and review 54 facial palsy patients under 12 years old who were admitted to Kurashiki Central Hospital between January 1991 and January 2002. Previously reported cases, congenital palsy patients and traumatic palsy patients were excluded from review.Case 1 was a 2-year-old girl, who was hospitalized due to left facial palsy. MRI revealed a well-enhanced mass both in the cerebellopontine (CP) angle and the spinal cord. The tumor in the spinal cord was pathologically diagnosed as an atypical teratoid-rhabdoid tumor, which probably caused metastasis from the CP angle to the spinal cord.Case 2 was a 5-year-old girl, who was admitted to the hospital with right facial palsy. At 3 years old, she developed right facial palsy but recovered one month later. At 4 years old, right arm and right leg palsy occurred, but recovered. MRI revealed arteriovenous malformation in the parietal lobe.Of 54 cases reviewed, 35 patients were diagnosed as having idiopathic palsy (Bells palsy), 11 as having viral infection, 7 as having otogenic disorder, 1 as having neoplasm. We were able to follow 42 cases over a prolonged period. Of these 42 cases, 39 cases recovered, and 3 cases did not recover.Facial palsy in children is considered to have a good prognosis, but it may be the initial manifestation of a life-threatening disorder such as intracranial vascular malformation or neoplasm. When neurologic findings in addition to facial palsy are manifested or suspected, it is important to search for an intracranial lesion. MRI is a very useful method of evaluating intracranial disease.