Nickel Enhances Zinc-Induced Neuronal Cell Death by Priming the Endoplasmic Reticulum Stress Response.

Trace metals such as zinc (Zn), copper (Cu), and nickel (Ni) play important roles in various physiological functions such as immunity, cell division, and protein synthesis in a wide variety of species. However, excessive amounts of these trace metals cause disorders in various tissues of the central nervous system, respiratory system, and other vital organs. Our previous analysis focusing on neurotoxicity resulting from interactions between Zn and Cu revealed that Cu2+ markedly enhances Zn2+-induced neuronal cell death by activating oxidative stress and the endoplasmic reticulum (ER) stress response. However, neurotoxicity arising from interactions between zinc and metals other than copper has not been examined. Thus, in the current study, we examined the effect of Ni2+ on Zn2+-induced neurotoxicity. Initially, we found that nontoxic concentrations (0-60 µM) of Ni2+ enhance Zn2+-induced neurotoxicity in an immortalized hypothalamic neuronal cell line (GT1-7) in a dose-dependent manner. Next, we analyzed the mechanism enhancing neuronal cell death, focusing on the ER stress response. Our results revealed that Ni2+ treatment significantly primed the Zn2+-induced ER stress response, especially expression of the CCAAT-enhancer-binding protein homologous protein (CHOP). Finally, we examined the effect of carnosine (an endogenous peptide) on Ni2+/Zn2+-induced neurotoxicity and found that carnosine attenuated Ni2+/Zn2+-induced neuronal cell death and ER stress occurring before cell death. Based on our results, Ni2+ treatment significantly enhances Zn2+-induced neuronal cell death by priming the ER stress response. Thus, compounds that decrease the ER stress response, such as carnosine, may be beneficial for neurological diseases.

Involvement of SAPK/JNK Signaling Pathway in Copper Enhanced Zinc-Induced Neuronal Cell Death.

Zinc (Zn) plays an important role in many organisms in various physiological functions such as cell division, immune mechanisms and protein synthesis. However, excessive Zn release is induced in pathological situations and causes neuronal cell death. Previously, we reported that Cu ions (Cu2+) markedly exacerbates Zn2+-induced neuronal cell death by potentiating oxidative stress and the endoplasmic reticulum stress response. In contrast, the stress-activated protein kinase/c-Jun amino-terminal kinase (SAPK/JNK) signaling pathway is important in neuronal cell death. Thus, in this study, we focused on the SAPK/JNK signaling pathway and examined its involvement in Cu2+/Zn2+-induced neurotoxicity. Initially, we examined expression of factors involved in the SAPK/JNK signaling pathway. Accordingly, we found that phosphorylated (ie, active) forms of SAPK/JNK (p46 and p54) are increased by CuCl2 and ZnCl2 co-treatment in hypothalamic neuronal mouse cells (GT1-7 cells). Downstream factors of SAPK/JNK, phospho-c-Jun, and phospho-activating transcription factor 2 are also induced by CuCl2 and ZnCl2 co-treatment. Moreover, an inhibitor of the SAPK/JNK signaling pathway, SP600125, significantly suppressed neuronal cell death and activation of the SAPK/JNK signaling pathway induced by CuCl2 and ZnCl2 cotreatment. Finally, we examined involvement of oxidative stress in activation of the SAPK/JNK signaling pathway, and found that human serum albumin-thioredoxin fusion protein, an antioxidative protein, suppresses activation of the SAPK/JNK signaling pathway. On the basis of these results, our findings suggest that activation of ZnCl2-dependent SAPK/JNK signaling pathway is important in neuronal cell death, and CuCl2-induced oxidative stress triggers the activation of this pathway.

Piezoelectric vibrator-stimulated potential and heart rate accelerations detected from the fetus.

OBJECTIVES: The fetus is well known to have a substantial capacity for sound recognition in the uterine environment. The aim of this study was to develop a sound stimulus system equipped with a piezoelectric vibrator (PV), record the PV-stimulated potential (PVSP) of the fetus and monitor changes of the fetal heart rate (FHR) under PV stimulation. METHODS: The relationship between the input voltage applied to a piezoelectric vibrator and the sound pressure generated in the uterus was calibrated based on a model of the maternal abdomen. Fourteen fetuses for the measurement of the PVSP and 22 fetuses for the measurement of the heart rate changes from low-risk pregnant women were recruited. RESULTS: The PVSP responses were obtained in 9 out of 14 fetuses. All the tested fetuses accelerated the FHR after the 2 kHz tone stimulation at 70 dB intensity generated by PV from 32 to 37 weeks gestational age. CONCLUSIONS: Using a newly developed sound stimulus system equipped with PV, the electric responses of a fetus recorded from electrodes placed on the mother's abdomen may be closely related to the auditory evoked response. Significant accelerations of FHR were objectively, accurately and readily obtained after the sound stimulation.

Surgical Management of Myringosclerosis over an Entire Perforated Tympanic Membrane by Simple Underlay Myringoplasty.

The aim of our study is to demonstrate the surgical management of myringosclerosis over a perforated whole tympanic membrane using simple underlay myringoplasty. Simple underlay myringoplasty with fibrin glue was performed in 11 ears with myringosclerosis over the entire tympanic membrane. The patients were one male and ten females and their mean age was 61.8 years (range, 40-73 yr). Surgical success was defined as an intact tympanic membrane 12 months after surgery. Closure of the perforation was successful in 10 (91%) of the 11 patients. Failure of the graft occurred in one patient who then underwent a revision procedure using her stored fascia in the outpatient clinic with a successful outcome. The overall success rate was 100%. Although this study included a small number of cases, removal of myringosclerosis at the edge of a perforation is a beneficial technique for simple underlay myringoplasty in terms of the success rate and postoperative hearing threshold, especially when myringosclerosis extends over the entire tympanic membrane.

Cavernous sinus thrombosis caused by contralateral sphenoid sinusitis: a case report.

OBJECTIVE: To report a rare case of unilateral cavernous sinus thrombosis caused by contralateral sphenoid sinusitis. CASE REPORT: A 33-year-old female visited our hospital for severe, right-sided, temporal headache, chemosis, periorbital edema, and proptosis. These signs were associated with congested erythematous nasal mucosa with purulent discharge from the right superior nasal meatus. Contrast enhanced CT showed dilated left superior ophthalmic vein, suggestive of thrombosis, contrast enhancement of the left cavernous sinuses, and dilation of cavernous sinus, indicating cavernous sinus inflammation. The right maxillary, ethmoid and sphenoid sinuses showed mucosal thickening and retention of purulent material. She was diagnosed with cavernous sinus thrombosis caused by contralateral sphenoid sinusitis. All clinical symptoms and signs improved after endoscopic sphenoidotomy and appropriate medical treatment. CONCLUSIONS: Sphenoiditis can cause contralateral cavernous sinus thrombosis. Early surgical sphenoidotomy and aggressive medical treatment are the cornerstones of successful management of this life-threatening complication.

Giant cell tumor of the temporal bone with direct invasion into the middle ear and skull base: a case report.

Giant cell tumor (GCT) is classified as a benign bone tumor, and it is frequently identified at the epiphysis of long bones and relatively rare in the temporal bone. For orthopedists expert at recognizing bone and soft tissue tumors, the diagnosis of GCT is relatively easy; however, since head and neck surgeons experience few cases of GCT, it may be difficult to diagnose when it occurs in the temporal bone. A 32-year-old man complained of left hearing loss, aural fullness, and tinnitus. Examination of the ear revealed a bulging tumor. Audiologic examination demonstrated conductive hearing loss of the left ear. Computer tomograph of the temporal bone showed a soft-tissue-density specification indicating bone destruction at the left temporal bone. The tumor invaded the skull base. Imaging examinations using magnetic resonance imaging revealed a nonhomogenous isosignal intensity area on T1 at the left temporal bone. After intravenous gadolinium, the mass showed unequal enhancement. This patient subsequently underwent surgery to remove the lesion using transmastoid and middle fossa approach. Pathological examinations from specimens of the tumor revealed characteristic of GCT. No clinical or radiological evidence of tumor recurrence was detected for 4 years.

Endoscopy-assisted transoral resection of the styloid process in Eagle's syndrome. Case report.

Eagle's syndrome is often associated with elongated styloid process or ossified stylohyoid or stylomandibular ligament. Patients with this syndrome present with recurrent cervicofacial pain. Surgical removal of the elongated styloid process is a standard treatment and can be accomplished through either a transoral or extraoral approach. Both approaches have advantages and disadvantages, and the best surgical approach remains controversial. In our case, the elongated styloid process was removed by transoral approach assisted by endoscopy. Endoscopy provides clear surgical view thus lessen the chance of neurovascular injury and other intraoperative complications. Endoscopy-assisted transoral resection is an optional alternative surgical procedure for Eagle's syndrome.

Gene transfer targeting mouse vestibule using adenovirus and adeno-associated virus vectors.

HYPOTHESIS: The present study assessed how to inject a gene into the mouse vestibule and which is the optimum gene to the mouse vestibule adenovirus (AdV) vector or adeno-associated virus (AAV) vector. BACKGROUND: Loss of vestibular hair cell is seen in various balance disorder diseases. There have been some reports concerning gene delivery to the mouse vestibule in recent years. To effectively induce transgene expression at the vestibule, we assessed the efficiency of inoculating the mouse inner ear using various methods. METHODS: We employed an AdV- and AAV-carrying green fluorescent protein using a semicircular canal approach (via a canalostomy) and round window approach. RESULTS: AAV injection via canalostomy induced gene expression at the hair cells, supporting cells, and fibrocytes at the vestibular organs without auditory or balance dysfunction, suggesting it was the most suitable transfection method. This method is thus considered to be a promising strategy to prevent balance dysfunction. CONCLUSION: AAV injection via canalostomy to the vestibule is the noninvasive and highly efficient transfection method, and this study may have the potential to repair balance disorders in human in the future.

Vestibular function of patients with profound deafness related to GJB2 mutation.

CONCLUSION: GJB2 mutations are responsible not only for deafness but also for the occurrence of vestibular dysfunction. However, vestibular dysfunction tends to be unilateral and less severe in comparison with that of bilateral deafness. OBJECTIVES: The correlation between the cochlear and vestibular end-organs suggests that some children with congenital deafness may have vestibular impairments. On the other hand, GJB2 gene mutations are the most common cause of nonsyndromic deafness. The vestibular function of patients with congenital deafness (CD), which is related to GJB2 gene mutation, remains to be elucidated. The purpose of this study was to analyze the relationship between GJB2 gene mutation and vestibular dysfunction in adults with CD. METHODS: A total of 31 subjects, including 10 healthy volunteers and 21 patients with CD, were enrolled in the study. A hearing test and genetic analysis were performed. The vestibular evoked myogenic potentials (VEMPs) were measured and a caloric test was performed to assess the vestibular function. The percentage of vestibular dysfunction was then statistically analyzed. RESULTS: The hearing level of all CD patients demonstrated a severe to profound impairment. In seven CD patients, their hearing impairment was related to GJB2 mutation. Five of the seven patients with CD related to GJB2 mutation demonstrated abnormalities in one or both of the two tests. The percentage of vestibular dysfunction of the patients with CD related to GJB2 mutation was statistically higher than in patients with CD unrelated to GJB2 mutation and in healthy controls.

Bacterial contamination of multiple-use atomizers commonly used in Japan.

Before performing transnasal fiberscopy to observe the nasal cavity, pharynx and larynx in outpatient clinics, nasal anesthetics and vasoconstrictive agents are routinely sprayed into the nares in order to improve patients' comfort. Bacterial contamination of the nozzles of Venturi principle atomizer barrels and their solutions after being used for multiple patients over a long-term period without cleaning is controversial. We evaluated the potential risk of atomizer-associated cross-infection by using atomizers commonly available in Japan that use compressed air to atomize medication. Eighteen of the 23 samples (78.3%) from the external nozzle tips of the atomizers resulted in positive bacterial cultures. These detected bacteria are suggested to be colonized in the nares and to cause bacterial contamination of the atomizer. Of the 25 samples obtained from the spray of the drug solutions, 11 samples showed positive bacterial culture, whereas 16 control samples produced no growth of bacteria. The present study demonstrated that the atomizer widely used in the outpatient ENT clinics in Japan has a potential risk of causing cross-infection of patients.

Treatment of idiopathic gustatory rhinorrhea by resection of the posterior nasal nerve.

We herein describe a case of 44-year old female who presented with a chief complaint of gustatory rhinorrhea from childhood, in which gustatory stimuli caused bilateral excessive, watery nasal secretion. No abnormality of taste acuity was observed. This disorder was presumably caused by faulty regenerated parasympathetic nerve fibers reaching the nasal mucosa or possibly, by a congenital condition. Nasal pretreatment with an anti-cholinergic drug clinically blocked the positive sugar-induced rhinorrhea, thus indicating that the gustatory rhinitis in this case was produced by foods that stimulate muscarinic receptors sensitive to atropine (probably on submucosal nasal glands). Although this syndrome can be treated prophylactically by the use of topical atropine, the patient preferred to undergo radical therapy and a resection of the posterior nasal nerve was performed through the middle meatus under endoscopic control. The resection of the nerve on both sides resulted in an almost complete inhibition of the sugar-induced rhinorrhea without serious complications. Although this disease is not life-threatening, it is socially embarrassing and troublesome to patients and surgical therapy is one of the accepted modalities.