Vestibular end organ injury induced by middle ear treatment with ferric chloride in rats.

Sensorineural hearing loss, ataxia, pyramidal signs, and vestibular deficits characterize superficial siderosis of the central nervous system. This study investigated changes in vestibular function, free radical formation, and phosphorylated cJun expression in the vestibular end organs after middle ear treatment with a ferric chloride (FeCl3) solution. A single injection of 70% FeCl3 solution into the unilateral middle ear cavity caused static vestibular symptoms, such as spontaneous nystagmus and head tilt. Asymmetric expression of c-Fos protein was observed in the bilateral vestibular nuclei and prepositus hypoglossal nuclei within 6 h after injection. Histopathologic examinations revealed partial hair cell loss, degeneration of the supporting stroma, and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells in the neuroepithelial layer of the crista ampullaris in FeCl3-treated animals. 5-(And-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester and diaminofluorescein-2 diacetate fluorescence and immunoreactivity for nitrotyrosine increased markedly in the sensory neuroepithelial layer and nerve bundles of the crista ampullaris after 2 h. Strong immunoreactivity for phospho-cJun and cJun was observed in the type I hair cells of the crista ampullaris 120 h after injection. Thus, a single short-term treatment with a high concentration of FeCl3 in the unilateral middle ear cavity can induce activation of intracellular signals for cJun protein and oxidative stress through the formation of reactive oxygen species and nitric oxide in vestibular sensory receptors, resulting in vestibular dysfunction. These results suggest that activation of intracellular signals for cJun protein and oxidative stress may be a key component of the pathogenesis of vestibular deficits in patients with superficial siderosis.

RETRACTED: Different bone mineral density in cervical and endometrial cancer.

Objectives Patients with cervical cancer have lower bone mass than women without cancer, whereas women with endometrial cancer have higher bone mineral density (BMD) than control subjects, possibly due to the prevalence of high body-fat mass. The aim of this study was to compare BMD in patients with cervical cancer, endometrial cancer and controls. Methods We analyzed and compared spinal and femoral BMD in 130 patients with cervical cancer, 68 with endometrial cancer, and 140 age-matched menopausal female control subjects. We also compared serum calcium, phosphorus, total alkaline phosphatase, osteocalcin, and urinary deoxypyridinoline levels. Results Compared with the control group, T-scores for some lumbar vertebrae (L4), the femoral neck, and Ward's triangle were lower in patients with cervical cancer, whereas only L4 T-scores were significantly lower in patients with endometrial cancer. Deoxypyridinoline levels were significantly lower in women with endometrial cancer (p < 0.002) than in women with cervical cancer, but no other biochemical variables differed among groups. Conclusions Cervical cancer was associated with lower BMD, especially in femoral BMD, and may be a risk factor for secondary osteoporosis. However, endometrial cancer generally seemed to have no damaging effect on bone except at L4. A further larger follow-up study in more populations is required to clarify these findings.

Prediction of response to entecavir therapy in patients with HBeAg-positive chronic hepatitis B based on on-treatment HBsAg, HBeAg and HBV DNA levels.

Quantitative hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) assays are emerging as effective tools of on-treatment predictors of response to antiviral agents, in addition to monitoring serum HBV DNA levels. However, the dynamic relationship between quantitative HBsAg, as well as HBeAg and HBV DNA, and the predictability of subsequent clinical outcomes during entecavir (ETV) therapy remain unclear. Eighty-two patients with HBeAg-positive chronic hepatitis B (CHB) received ETV therapy for ≥3 years. Virologic response (VR) after 3 years of ETV therapy was achieved in 73 (89.0%) patients. Among baseline and on-treatment factors, on-treatment HBV DNA levels performed better with respect to the prediction of response than HBsAg and HBeAg levels. Especially, the performance of absolute values of HBV DNA with respect to response was superior to HBV DNA decline from the baseline. The best predictive value was an absolute HBV DNA level of 2.3 log(10) IU/mL at month 6 (areas under the curve [AUROC], 0.977; 95% CI, 0.940-1.000; P < 0.001). HBeAg seroconversion after 3 years of therapy was achieved in 26 (31.7%) patients. On-treatment HBeAg levels performed better with respect to the prediction of seroconversion than HBsAg and HBV DNA levels. The best cut-off value for the HBeAg level at month 12 for the prediction of seroconversion was 0.62 log(10) PEIU/mL. Although the HBsAg level at baseline is often used to predict the antiviral potency of entecavir, on-treatment HBV DNA and HBeAg levels are more helpful for prediction of subsequent clinical outcomes in HBeAg-positive CHB patients with entecavir treatment.

Combined motor- and somatosensory-evoked potential monitoring for spine and spinal cord surgery: correlation of clinical and neurophysiological data in 85 consecutive procedures.

STUDY DESIGN: Prospective study. OBJECTIVES: The primary objective of neurophysiological monitoring during surgery is to prevent permanent neurological sequelae. To avoid neurological injury, we applied somatosensory-evoked potentials (SEPs) and/or motor-evoked potentials (MEPs). We evaluated whether the combination of SEP and MEP for spinal surgery may be beneficial. SETTING: Asian Medical Center, University of Ulsan College of Medicine, Seoul, Korea. METHODS: Combined SEP/MEP monitoring was attempted in 100 consecutive procedures for spinal operations. Trains of transcranial electrical stimulation over the motor cortex were used to elicit MEPs from the muscles of the upper/lower limbs. The tibial and median nerves were stimulated to record SEP. RESULTS: Combined SEP/MEP recording was successfully achieved in 85 of 100 operations. In 61 of 85 operations (71%), SEP and MEP were stable, and all patients remained neurologically intact after surgery. Significant MEP changes were recorded in 20 operations, either combined with (n=4) or without (n=16) SEP changes. In 7 of these 20 operations, MEP recovered to some extent after surgical intervention, and these patients showed no neurological changes. In the remaining 13 operations, MEP did not recover and the patients had a transient (n=4) or a permanent (n=3) motor deficit. Significant SEP changes with stable MEP were observed in four operations, all of which were not related to postoperative motor deficit. CONCLUSION: Combined SEP/MEP monitoring provided higher sensitivity and higher positive/negative predictive value than single-modality monitoring techniques. Detection of MEP changes and adjustment of surgical strategy may prevent irreversible pyramidal tract damage.

Cerebellar infarction presenting isolated vertigo: frequency and vascular topographical patterns.

OBJECTIVE: To determine the frequency of cerebellar infarction mimicking vestibular neuritis (VN), the pattern of clinical presentation, and the territory of the cerebellar infarction when it simulates VN. METHODS: We studied 240 consecutive cases of isolated cerebellar infarction in the territories of the cerebellar arteries diagnosed by brain MRI from the acute stroke registry at the Keimyung University Dongsan Medical Center. RESULTS: We identified 25 patients (10.4%) with isolated cerebellar infarction who had clinical features suggesting VN. Two types of cerebellar infarction simulating VN were found: isolated spontaneous prolonged vertigo with imbalance as a sole manifestation of cerebellar infarction (n = 24) and isolated spontaneous prolonged vertigo with imbalance as an initial manifestation of cerebellar infarction (n = 1) followed by delayed neurologic deficits 2 days after the onset. The cerebellar infarction territory most commonly involved was the medial branch of the posterior inferior cerebellar artery territory (24/25: 96%), followed by the anterior inferior cerebellar artery territory (1/25: 4%). None of patients with infarcts in the territory of the superior cerebellar artery or multiple cerebellar arteries showed isolated spontaneous prolonged vertigo. CONCLUSIONS: Cerebellar infarction simulating vestibular neuritis is more common than previously thought. Early recognition of the pseudo-vestibular neuritis of vascular cause may allow specific management.

Effects of acute hypotension on neuronal activity in the medial vestibular nuclei of rats.

The role of peripheral vestibular receptors in acute hypotension was investigated in anesthetized rats. In animals with intact labyrinths, acute hypotension induced by either i.v. infusion of sodium nitroprusside or hemorrhage produced excitation of electrical activity in two-thirds of type I neurons and inhibition in two-thirds of type II neurons recorded in the medial vestibular nuclei. In unilaterally labyrinthectomized animals, two-thirds of type I neurons ipsilateral to the lesion showed an inhibitory response, and two-thirds of contralateral type I neurons showed an excitatory response after the induction of acute hypotension. The response patterns of type II neurons were opposite to those of type I neurons. These results suggest that blood flow changes are detected by peripheral vestibular receptors, and that this might suggest a mechanism for control of blood pressure.

Early development of vasogenic edema in experimental cerebral fat embolism in cats: correlation with MRI and electron microscopic findings.

RATIONALE AND OBJECTIVES: To evaluate the magnetic resonance imaging and electron microscopic findings of the hyperacute stage of cerebral fat embolism in cats and the time needed for the development of vasogenic edema. METHODS: Magnetic resonance imaging was performed at 30 minutes (group 1, n = 9) and at 30 minutes and 1, 2, 4, and 6 hours after embolization with triolein (group 2, n = 10). As a control for group 2, the same acquisition was obtained after embolization with polyvinyl alcohol particles (group 3, n = 5). Magnetic resonance images were analyzed qualitatively and quantitatively. Electron microscopic examination was done in all cats. RESULTS: In group 1, the lesions were iso- or slightly hyperintense on T2-weighted (T2W) and diffusion-weighted (DWIs) images, hypointense on the apparent diffusion coefficient (ADC) map image, and markedly enhanced on the gadolinium-enhanced T1-weighted images (Gd-T1WIs). In group 2 at 30 minutes, the lesions were similar to those in group 1. Thereafter, the lesions became more hyperintense on T2WIs and DWIs and more hypointense on the ADC map image. The lesions were enhanced on Gd-T1WIs at all acquisition times. In group 3, the lesions showed mild hyperintensity on T2WIs at 6 hours but hypointensity on the ADC map image from 30 minutes, with a tendency toward a greater decrease over time. The lesions were not enhanced on Gd-T1WIs at any time point. Electron microscopic findings revealed discontinuity of the capillary endothelial wall, perivascular and interstitial edema, and swelling of glial and neuronal cells in groups 1 and 2. Cellular swelling and interstitial edema were more prominent in group 2. In group 3, interstitial edema was seen; however, discontinuity of the endothelial wall was absent. CONCLUSIONS: The lesions were hyperintense on T2WIs and DWIs, hypointense on the ADC map image, and enhanced on Gd-T1WIs. On electron microscopy, the lesions showed cytotoxic and vasogenic edema with disruption of the blood-brain barrier. Vasogenic edema seems to develop within 30 minutes in cerebral fat embolism in cats.

Nitric oxide production by high molecular weight water-soluble chitosan via nuclear factor-kappaB activation.

High molecular weight water-soluble chitosan (WSC), having an average molecular weight of 300000 Da and a degree of deacethylation over 90%, can be produced using a simple multi-step membrane separation process. In this study, the effect of WSC on the production of nitric oxide (NO) in RAW 264.7 macrophages was evaluated. Water-insoluble chitosan alone has been previously shown to exhibit in vitro stimulatory effect on macrophages NO production. However, WSC had no effect on NO production by itself. When WSC was used in combination with recombinant interferon-gamma (rIFN-gamma), there was a marked cooperative induction of NO synthesis in a dose-dependent manner. The optimal effect of WSC on NO synthesis was shown 24 h after treatment with rIFN-gamma. The increased production of NO from rIFN-gamma plus WSC-stimulated RAW 264.7 macrophages was decreased by the treatment with N(G)-monomethyl-L-arginine (N(G)MMA). The increase in NO synthesis was reflected, as an increased amounts of inducible NO synthase protein. In addition, synergy between rIFN-gamma and WSC was mainly dependent on WSC-induced tumor necrosis factor-alpha (TNF-alpha) and nuclear factor-kappaB (NF-kappaB) activation. The present results indicate that the capacity of WSC to increase NO production from rIFN-gamma-primed RAW 264.7 macrophages is the result of WSC-induced TNF-alpha secretion via the signal transduction pathway of NF-kappaB activation.

Identification of phosphorylated form of cAMP/calcium response element binding protein expression in the brain stem nuclei at early stage of vestibular compensation in rats.

The present study was aimed at evaluating the time-dependent expressions of phosphorylated forms in the cAMP/calcium response element binding protein (pCREB) known to be one of transcription factors for immediate early genes in the brain stem nuclei of Sprague-Dalwey rats. Animals received surgical ablation of right peripheral vestibular labyrinth through a ventral approach. Immunohistochemical staining and digital image analysis systems were used to observe pCREB expressions in neuronal cells of the brain stem nuclei. The number of pCREB labeling neurons were increased with time, and peaked in the vestibular nuclear complex (VNC) bilaterally 1 h after unilateral labyrinthectomy (UL). In addition, high levels of phosphorylated CREB-like immunoreactivity (pCREB-LI) were also observed in bilateral cerebellum, olivary nuclear complex, and medullary nuclei. There was a rapid reduction of pCREB-LI in contralateral VNC but a slow reduction in the ipsilateral side 2 h after UL, causing an asymmetric number of pCREB labeling neurons between bilateral VNC (P<0.05). Thereafter pCREB-LI in bilateral VNC decreased to a very low level and returned to basal level 24 h after UL. These results suggest that the activation of the cAMP/calcium response element binding protein plays a role in the initial events of vestibular compensation in rats.

Molecular cloning and characterization of splice variants of human RAD50 gene.

In this report, splice variants of human RAD50 (hRAD50) were cloned and characterized. A Northern blot survey identified two transcripts that hybridized to a hRAD50 cDNA clone, an upper faint band (5.9kb) and lower dense band (4.6kb). cDNA clones (hRAD50-2, 4.6kb) encompassing the entire hRAD50 transcript but having a shorter 3'-untranslated region (3'UTR) than the previously reported hRAD50-1 cDNA (5.9kb; Dolganov, G.M., Maser, R.S., Novikov, A., Tosto, L., Chong, S., Bressan, D.A., Petrini, J.H.J., 1996. Human Rad50 is physically associated with human Mre11: Identification of a conserved multiprotein complex implicated in recombinational DNA repair. Mol. Cell. Biol. 16, 4832-4841.) were isolated. The presence of AU-rich sequences in the 3'UTR of hRAD50-1, which define mRNA instability and Northern results, suggest that hRAD50-2 is the major transcript of hRAD50. A third alternative splice variant that lacks the ATP-binding domain was also identified (hRAD50-3, approximately 4.5kb). Expression of hRAD50-3 transcript was detected in all tissues examined by RT-PCR (reverse transcriptase-polymerase chain reaction) and nested DNA-PCR analyses. Expression of hRAD50 partially rescued the MMS (methyl methanesulfonate)-sensitive phenotype in rad50 mutant yeast, whereas hRAD50-3 did not show complementation. These data suggest that the hRAD50-3 does not repair DNA double-strand breaks most likely due to its inability to bind ATP, and to bind damaged DNA. The existence of these alternative splice forms is potentially important in regulation of the biological activity of the DNA recombinational repair gene, hRAD50.

Effects of galvanic stimulation of the mastoid process on the gastric motility induced by caloric stimulation.

The effects of galvanic stimulation to the mastoid portion on the vestibuloautonomic symptoms induced by caloric stimulation, such as nausea, vomiting, and vertigo, were evaluated in this study. Gastric motility was measured by electrogastrography (EGG) in 20 healthy volunteers (11 male and nine female) aged 20-30 (average: 25.4) years. Electrical stimulation of the mastoid process with 1.0-3.0 mA, 1.0 ms, 100 Hz was applied using a bipolar-biaural method during caloric stimulation of the external auditory canal. The dominant frequency and power of EGG were determined using running spectral frequency analysis and the time-course of EGG was evaluated in a pseudo three dimensional graphic. Frequency of EGG was classified into normogastria with 3 cpm, bradygastria with lower than 3 cpm, and tachygastria with higher than 3 cpm. At quiescent period, normogastria was 78.7 +/- 3.7%, bradygastria 5.0 +/- 1.1%, and tachygastria 16.4 +/- 3.7%. Caloric stimulation with warm water in the unilateral ear and cold water in the contralateral ear elicited vestibuloautonomic symptoms, with accompanied decreases in normogastria (57.7 +/-4.6%, P < 0.01) and increases in tachygastria (34.8 +/- 4.8%, P < 0.01). Cathodal stimulation to the mastoid process ipsilateral to cold water irrigation during caloric stimulation restored normal pattern of gastric motility: normogastria in 77.1 + 5.3% and tachygastria in 19.3 +/- 4.7%, and relieved vestibuloautonomic symptoms. Cathodal stimulation to the inhibited vestibular system ameliorates the vestibular symptoms induced by caloric stimulation.

Effect of MK801 on cFos-like protein expression in the medial vestibular nucleus at early stage of vestibular compensation in uvulonodullectomized rats.

The purpose of this study was to evaluate the effect of uvulonodullectomy (UNL) on the expression of cFos-like protein (FLP) in the medial vestibular nucleus (MVe) during vestibular compensation and effect of MK801, an N-methyl-D-aspartate (NMDA) antagonist, on FLP expression in the brain stem nuclei at 6 h after unilateral labyrinthectomy (ULX) with UNL in Sprague-Dawley rats. Immunohistochemical staining was performed to visualize FLP in the brain stem nuclei and FLP-positive cells were counted by image analyzer. Lesion-induced asymmetric expression of FLP in the bilateral MVe was observed and maintained up to for 72 h in the ULX group, and 120 h in the UNL + ULX group. Moreover, spatial pattern of FLP expression in the bilateral MVe exhibited the marked difference between the ULX and UNL + ULX groups. MK801 treatment 6 h after ULX showed significant increase in the number of FLP in contralateral MVe (cMVe) of the ULX group, but decrease in cMVe of the UNL + ULX group. These results suggest that the lesion of vestibulocerebellum delays the temporal recovery of FLP expression in MVe and the vestibulocerebellar NMDA receptors relate to FLP expression in MVe.

Role of vestibulocerebellar N-methyl-D-aspartate receptors for behavioral recovery following unilateral labyrinthectomy in rats.

The purpose of current study was to elucidate whether vestibulocerebellar N-methyl-D-aspartate (NMDA) receptors are implicated in MK801 induced vestibular decompensation. Sprague-Dawley rats were unilaterally labyrinthectomized (ULX) and some of them were uvulonodullectomized before ULX (UNL + ULX). Number of spontaneous nystagmus (SN) and degree of head deviation (HD) were used as a parameter of behavioral recovery. MK801 treatment 6 h after ULX produced significant increases in SN and decreased HD in ULX rats, indicating decompensation. In marked contrast, however, MK801 treatment resulted in a great reduction of SN and HD in UNL + ULX rats; suggesting involvement of vestibulocerebellar NMDA receptors in MK801 induced decompensation during early stage of vestibular compensation.

Effect of sensory deprivation or electrical stimulation on acute vestibular symptoms following unilateral labyrinthectomy in rabbit.

The effect of sensory deprivation or electrical stimulation on vestibular compensation was investigated for 7 days after unilateral labyrinthectomy (ULX) in 50 rabbits. Eye movements induced by sinusoidal rotation of the whole body and spontaneous nystagmus were measured for vestibulo-ocular compensation, and head deviation was measured for vestibulospinal compensation. The rabbits were divided into 4 groups: one with ULX only (LX only), ULX with bilateral tarsorrhaphy (LX+TX), ULX with cervical dorsal root ganglionectomy (LX+GX), and a group stimulated electrically on the lesion-sided vestibular system with square pulse for 8 h/day (LX+ES). In LX only, the frequency of spontaneous nystagmus was 2.93 +/- 0.19 beats/sec just after ULX, declining to zero in 4 days. In eye movements induced by sinusoidal rotation on the 7th day after ULX, directional preponderance was 24-43% and gain decreased to 32-48% by rotation toward the intact side and 17-29% by rotation toward the lesion side, compared with that before ULX. Roll head tilt and yaw head tilt were 82 +/- 9 degrees, 45 +/- 6 degrees, respectively, on the 7th day. Recovery of vestibulo-ocular reflex and head deviation was delayed in LX+TX and LX+GX compared with that in ULX only, but recovery was enhanced in LX+ES. Therefore, in this study, electrical stimulation of the lesion side seemed to have a favorable effect on suppression of acute vestibular symptoms induced by unilateral vestibular lesion.

Spatial organization of neck and vestibular reflexes acting on the forelimbs of the decerebrate cat.

EMG recording was used to study the spatial organization of vestibular and tonic neck reflexes acting on forelimb and shoulder muscles of the decerebrate cat. Neck reflexes were studied in preparations with intact labyrinths as well as those with acute or chronic labyrinthectomies. Reflexes were described by response vectors whose orientation component is aligned with the optimal excitatory direction of tilt or head rotation. A muscle's vector orientation remained reasonably stable over a period of hours, although there was sometimes drift at the beginning or end of an experiment. Orientation of muscle response vectors did not change systematically with stimulus frequency of 0.05-2.0 Hz. For vestibular reflexes this is so, although their dynamics are consistent with convergent input from semicircular canals and otolith organs. Regardless of the preparation, a consistent reflex pattern emerged. Vestibular reflexes are characterized by response vector orientation near ear-down roll. Neck vector orientation lies in the opposite direction from the vestibular vector but typically lies further from the roll plane: Nose-up pitch is excitatory for the shoulder muscles supra- and infraspinatus, and for the medial and lateral heads of triceps, whereas nose-down pitch excites the long head of triceps. Our results generally agree with the pattern proposed by Roberts (28) for neck reflexes but disagree in part with his proposed pattern of vestibular reflexes; we did not see the expected consistent excitation by nose-down pitch.

Directional sensitivity of, and neck afferent input to, cervical and lumbar interneurons modulated by neck rotation.

In response to neck rotation of decerebrate, acutely labyrinthectomized cats, interneurons in C4 respond far more frequently to nose-up than to nose down pitch, whereas the reverse is true for interneurons in L3-L4. These directional sensitivities resemble the pattern of extensor excitation in the tonic neck reflex. C4 neurons receiving short latency excitation from the C2 dorsal root ganglion due to intraspinal pathways have a distribution of directional sensitivities to pitch stimuli that is similar to that of the whole population. The directional sensitivities of C4 neurons with late excitation, which may be due to supraspinal loops, are more broadly distributed.