Telbivudine-Induced Myopathy: Clinical Features, Histopathological Characteristics, and Risk Factors.

BACKGROUND AND PURPOSE: Oral nucleos(t)ide analogs (NAs) are the mainstay treatment for chronic hepatitis B (CHB). Myotoxicity is an important extrahepatic effect related to NA treatment. Telbivudine is the NA for CHB that is frequently associated with muscle-related side effects. The risk factors for telbivudine-induced myopathy (TIM) are not yet clear. METHODS: This study characterized the clinical, magnetic resonance images (MRI), and pathological features of 12 TIM cases. A group of telbivudine-tolerant (TT) patients with CHB who received regular telbivudine treatment during the same period without the occurrence of myopathy was collected. Demographic and clinical factors were compared between the patients with TIM and the TT controls. Factors independently associated with TIM were identified using logistic regression analysis. RESULTS: The patients with TIM (males/females: 7/5, mean age: 57 years) developed myopathy after using telbivudine for a median period of 19.5 months. Muscle histopathology revealed abnormal proliferation, subsarcolemmal or sarcoplasmic accumulations, and ultrastructural defects of mitochondria. When compared with TT cases, patients with TIM had a lower estimated glomerular filtration rate and were more frequently positive for hepatitis B e antigen (HBeAg). CONCLUSIONS: Mitochondrial abnormalities are characteristic histopathological features, and impaired renal function and HBeAg positivity are risk factors for TIM. Telbivudine-induced mitochondrial dysfunction and immune activation related to mitochondrial damage and HBeAg serostatus changes may underlie TIM. Constant clinical surveillance of myopathy during telbivudine treatment is needed due to the significant latency of its development. Dose adjustment for impaired renal function does not eliminate the risk of TIM occurrence.

High-fat diet reduces novelty-induced expression of activity-regulated cytoskeleton-associated protein.

Chronic high-fat-diet (HFD) consumption can lead to the development of brain insulin resistance, which then exerts deleterious effects on learning and memory. Activity-regulated cytoskeleton-associated protein (Arc) is a memory-related protein, and its expression can be induced by insulin stimulation. In HFD-fed animals, their basal Arc protein levels in cerebral cortex and hippocampus are reduced. However, the effects of HFD on novelty-induced Arc protein expression that is important for cognitive function is still unknown. In the present study, after feeding HFD (60% kcal from fat) for 5 weeks, mice developed brain insulin resistance and had a significant reduction in the novelty-induced but not the basal Arc protein levels in their hippocampi. Further experiments were performed in primary rat hippocampal neurons. The results show that, under the condition of neuronal insulin resistance, acute insulin stimulation induced less activation of the phosphatidylinositol 3-kinase/protein kinase B/p70 ribosomal S6 kinase (PI3K/Akt/p70S6K) pathway, resulting in reduced induction of Arc protein expression. Accordingly, it is suggested that following HFD feeding, the reduction in novelty-induced Arc protein expression in animal's hippocampus is probably related to a suppressed activation of the PI3K/Akt/p70S6K pathway due to the existence of brain insulin resistance.

Factors affecting the health-related quality of life of caregivers of patients with muscular dystrophy.

Muscular dystrophy (MD) is a group of progressive muscle weakness diseases. The caregiver burden, increasing as the disease progresses, can be associated with impaired health-related quality of life (HRQOL). The aims of this study were to investigate the HRQOL in caregivers of patients with MD and identify the factors associated with HRQOL. A cross-sectional assessment of caregiver HRQOL was performed with the Short Form-36 and compared with norms. The factors affecting HRQOL were investigated by patient and caregiver characteristics. The Muscular Dystrophy Functional Rating Scale was used to assess the functional status (mobility, basic activities of daily living, arm function, and impairment) of patients. The demographic data and social interaction activities of caregivers were assessed. Caregivers (n = 62) had poor HRQOL. Caregiver HRQOL was associated with the patient's functional status, especially in the domains of Vitality and Mental Health. Numerous visits by neighbors and close friends of the caregiver family indicated better HRQOL (in the body pain, general health, vitality, role emotion and mental health domains). Caregiver HRQOL was associated with caregiver education level, while patient age, caregiver age, length of caregiving, and family income were not. These findings demonstrate that caregivers have poor HRQOL, and the mental domain of quality of life is associated with the patient's functional status, social interaction, and caregiver education level. We suggest that rehabilitation programs focus on caregiver HRQOL, promote the patient's functional status with assistive technology, enhance professional caring techniques, and encourage participation in social groups to improve caregiver HRQOL.

Quality of life of patients with Duchenne muscular dystrophy: from adolescence to young men.

PURPOSE: This study investigated quality of life (QOL) in adolescent and young men with Duchenne muscular dystrophy (DMD). METHODS: Health-related QOL and global QOL were assessed with the Short Form 36 (SF-36) and World Health Organization Quality of Life-BREF (WHOQOL-BREF). Associations between functional status and QOL were assessed. RESULTS: All domains of the SF-36 were below Taiwan norms (effect size: -14.2 to -0.5), especially Physical Function, Role Physical, and Social Function. Three of the four domains of the WHOQOL-BREF were below Taiwan norms (effect size: -2.0 to -0.7). The Physical Function of the SF-36 was moderately correlated with functional status (mobility, basic activities of daily living, and arm function). The Social Function of the SF-36 and Social Relationships of the WHOQOL-BREF were also moderately correlated with functional status (impairment, basic activities of daily living, and arm function). CONCLUSION: The adolescent and young men with DMD had poor health-related and global QOL. Poor QOL was related to both physical condition and social health. We suggest that rehabilitation programs focus on using assistive devices to facilitate arm function and encouraging participation in social activities to improve the QOL of patients with DMD. Implications for rehabilitation Duchenne muscular dystrophy (DMD) is a progressive muscle weakness disease that not only impacts physical health but also leads to poor quality of life in many domains. A valuable rehabilitation goal for patients with DMD is to encourage participation in social activities. Medical care and educational programs should plan a formal transition processes for patients with DMD from pediatric to adult care to maximum their quality of life. Arm function is associated with many domains of global quality of life, so a key element in improving quality of life may be to improve arm function.

The Cholinergic Signaling Responsible for the Expression of a Memory-Related Protein in Primary Rat Cortical Neurons.

Cholinergic dysfunction in the brain is closely related to cognitive impairment including memory loss. In addition to the degeneration of basal forebrain cholinergic neurons, deficits in the cholinergic receptor signaling may also play an important role. In the present study, to examine the cholinergic signaling pathways responsible for the induction of a memory-related postsynaptic protein, a cholinergic agonist carbachol was used to induce the expression of activity-regulated cytoskeleton associated protein (Arc) in primary rat cortical neurons. After pretreating neurons with various antagonists or inhibitors, the levels of carbachol-induced Arc protein expression were detected by Western blot analysis. The results show that carbachol induces Arc protein expression mainly through activating M1 acetylcholine receptors and the downstream phospholipase C pathway, which may lead to the activation of the MAPK/ERK signaling pathway. Importantly, carbachol-mediated M2 receptor activation exerts negative effects on Arc protein expression and thus counteracts the enhanced effects of M1 activation. Furthermore, it is suggested for the first time that M1-mediated enhancement of N-methyl-D-aspartate receptor (NMDAR) responses, leading to Ca(2+) entry through NMDARs, contributes to carbachol-induced Arc protein expression. These findings reveal a more complete cholinergic signaling that is responsible for carbachol-induced Arc protein expression, and thus provide more information for developing treatments that can modulate cholinergic signaling and consequently alleviate cognitive impairment. J. Cell. Physiol. 231: 2428-2438, 2016. © 2016 Wiley Periodicals, Inc.

The implication of integrated training program for medical history education.

BACKGROUND: A full spectrum of medical education requires not only clinical skills but also humanistic qualities in the medical professionals, which can be facilitated by an integrated training program. An integrated project was created to improve one's medical intellectual and communication competence and to enable them to become docents who can perform well, as well as for development of their humanitarian nature. The aim of this study was to suggest an integrated program that provided approaches for creating positive effects in medical history education. METHODS: Taiwan Medical Museum conducted a project on medical history lessons and docent training program; 51 participants (24 male and 27 female) attended this plan. Targets took pre-tests before lectures, attended courses of medical history, and then took post-tests. Next, they received a series of lessons on presentation skills and practiced for guiding performance. After all the training processes, the attendees succeeded in all evaluations in order to guide exhibition visitors. Data were analyzed using paired t test. RESULTS: Two types of assessments were followed, i.e., cognitive examination and guiding practice, and both were related to good performance. Reliability (Cronbach's α) was 0.737 for the cognitive examination and 0.87 for the guiding evaluation. It indicated that the integrated program for docent training resulted in a significant difference (p ≦ 0.0001). CONCLUSION: The participants demonstrated better achievement and knowledge acquisition through the entire process, which led to great performance when approached by the visitors. The whole project helped to shape up a good docent and to accumulate positive learning experiences for medical professionals as well. Therefore, an integrated program is recommended to medical history education in the future.

Di-(2-ethylhexyl)-phthalate reduces MyoD and myogenin expression and inhibits myogenic differentiation in C2C12 cells.

The purpose of this study was to investigate the effects of di-(2-ethylhexyl) phthalate (DEHP) treatment on MyoD and myogenin expression and myotube formation in the murine C2C12 cells. Myogenic differentiation is principally regulated by activities of myogenic regulatory factors, such as MyoD and myogenin, leading the elongation and fusion of mononucleated myoblasts into multinucleated myotubes. In the present study, myogenic differentiation of C2C12 cells was induced by serum deprivation with medium containing vehicle or DEHP (10, 100, 1,000 µg/ml) for 5 days. Using 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay clearly demonstrated cell viability was not affected by DEHP at any given dose. At the dose of 1,000 µg/ml DEHP, the elongation of multinucleated myotubes, and the percent of nuclei incorporated into myosin heavy chain (MyHC)-stained myotubes were markedly reduced. In addition, immunoblotting revealed expression of muscle specific marker MyHC, as well as myogenic regulatory factors MyoD and myogenin, were reduced in DEHP-treated myotubes during myogenic differentiation. Taken together, the results showed that DEHP may impair myogenic differentiation through repression of myogenic regulatory factors, such as MyoD and myogenin, resulting in a reduction of MyHC expression. This in vitro study suggests that DEHP may be an environmental risk factor for myogenesis.

The medicolegal issue of tissue plasminogen activator in ischemic stroke: a review of judiciary decrees in Taiwan.

PURPOSE: Tissue plasminogen activator (tPA) was approved by the Food and Drug Administration for ischemic stroke treatment since 1996 at the United States of America and also 2002 at Taiwan. Since after it is strongly advertised for a promising benefit to early thrombolysis that is further echoed by a recommendation in clinical guidelines from multiple medical associations in worldwide. Because of an overwhelming data of positive benefit collected in the evidence-based medicine database, legal dispute subsequently occurs when tPA is failed to be administrated in appropriate time. METHODS: In order to elucidate the legal viewpoint for tPA used in ischemic stroke, a review of the domestic judiciary decrees regarding this issue was conducted. Cases in Taiwan were executed from the open access database of the Judicial Yuan, Taiwan. The background, legal dispute and judgment of each case were analyzed. RESULTS: Till August, 2010, there were 6 cases in Taiwan. All cases occurred after 2003. The causes of disputes were a loss of chance for thrombolysis due to a delay of diagnosis (4 cases, 67%) and a failure of thrombolytic treatment after a diagnosis of ischemic stroke (2 cases, 23%). All cases were presented to non-neurologists at initial. Five cases expired or terminated into vegetation before litigation. CONCLUSION: A failure of early diagnosis or treatment after a diagnosis of ischemic stroke are important for medicolegal dispute in tPA usage, which is expected to become prevalent in Taiwan in future. A fatal or poor outcome may be a triggering factor for litigation. Therefore, an improvement of the knowledge and practice to increase early diagnosis of ischemic stroke is the key factor for reducing medicolegal issue regarding tPA use in ischemic stroke. This is particularly true for non-neurologist physicians.

Dichotic multiple-frequency auditory steady-state responses in evaluating the hearing thresholds of occupational noise-exposed workers.

An objective, fast, and reasonably accurate assessment test that allows for easy interpretation of the responses of the hearing thresholds at all frequencies of a conventional audiogram is needed to resolve the medicolegal aspects of an occupational hearing injury. This study evaluated the use of dichotic multiple-frequency auditory steady-state responses (Mf-ASSR) to predict the hearing thresholds in workers exposed to high levels of noise. The study sample included 34 workers with noise-induced hearing impairment. Thresholds of pure-tone audiometry (PTA) and Mf-ASSRs at four frequencies were assessed. The differences and correlations between the thresholds of Mf-ASSRs and PTA were determined. The results showed that, on average, Mf-ASSR curves corresponded well with the thresholds of the PTA contours averaged across subjects. The Mf-ASSRs were 20±8dB, 16±9dB, 12±9dB, and 11±12dB above the thresholds of the PTA for 500Hz, 1,000Hz, 2,000Hz, and 4,000Hz, respectively. The thresholds of the PTA and the Mf-ASSRs were significantly correlated (r=0.77-0.89). We found that the measurement of Mf-ASSRs is easy and potentially time saving, provides a response at all dichotic multiple frequencies of the conventional audiogram, reduces variability in the interpretation of the responses, and correlates well with the behavioral hearing thresholds in subjects with occupational noise-induced hearing impairment. Mf-ASSR can be a valuable aid in the adjustment of compensation cases.

Activation of Trim17 by PPARγ is involved in di(2-ethylhexyl) phthalate (DEHP)-induced apoptosis on Neuro-2a cells.

Di-(2-ethylhexyl) phthalate (DEHP) is widely used as a plasticizer in plastics. Its reproductive toxicity and teratogenic effects are well known. DEHP can cause liver damage and peroxisome proliferation, as well as carcinogenesis. Animal study has shown that DEHP causes neurodegeneration in rat brain. Prenatal exposure to DEHP disrupts brain development and decreases brain weight in rats. But its mechanism of action in the brain is not clear. This study used a neuroblastoma cell line, Neuro-2a cells, to investigate the toxic effect of DEHP. The results revealed that DEHP inhibits cell proliferation, activate caspase-3, induce apoptosis in a dose and time dependent manner, and activate expression of the PPARγ and Trim17 protein. Administration of the PPARγ agonist (troglitazone) enhanced DEHP-induced Trim17 protein expression and this enhancement could be reversed by the PPARγ antagonist (GW9662). These results suggest that DEHP activates the Trim17 protein via PPARγ leading to cleavage pro-caspase-3 and apoptosis. This finding may account for the central nervous system toxicity of DEHP and implies DEHP can impair fetal brain development.

Rapid progressive course of later-onset Pompe disease in Chinese patients.

BACKGROUND: Pompe disease presents with a wide variety of phenotypes ranging from a fatal disease in infancy (the infantile-onset form) to other milder later-onset forms. Currently, the clinical manifestations in Chinese patients with later-onset Pompe disease are still not well understood. METHODS: Fifteen Chinese patients who were clinically diagnosed with Pompe disease at later than one year of age at the National Taiwan University Hospital from 1993 to 2009 were included in this study. Confirmatory diagnosis included both biochemical and molecular tests. Patient outcomes after recombinant human acid α-glucosidase (GAA) therapy were also evaluated by assessing the percentage of predicted forced vital capacity in the upright position, hours of daily ventilator use, and the functional status change using Walton Gardner Medwin Scale. RESULTS: The median age at symptom onset was 15 (12-35)years, and the median age at diagnosis was 21 (10-38)years. At the time of diagnosis or shortly after, 8 patients (53%) required mechanical ventilation. A quadriceps muscle biopsy from a 13-year-old boy already showed extensive glycogen storage and muscle fiber destruction. Mutation analysis revealed that the two dual mutations in the GAA gene c.[1935C>A; 1726G>A] (p.[D645E; G576S]) and c.[2238G>C; 1726G>A] (p.[W746C; G576S]) represented 66.5% of the mutated chromosomes. Using mutagenesis, we showed that the p.G576S pseudodeficiency mutation significantly decreased the residual enzyme activity of p.W746C. Most patients responded poorly to recombinant human GAA. CONCLUSIONS: Chinese patients with later-onset Pompe disease often showed onset of symptoms in their second decade of life with rapid disease progression, which is probably due to a specific pattern of GAA gene mutation. Therefore, early diagnosis and early treatment would be necessary to improve the prognosis of these patients.

Predicting hearing thresholds and occupational hearing loss with multiple-frequency auditory steady-state responses.

OBJECTIVE: An objective investigation is needed to verify the existence and severity of hearing impairments resulting from work-related, noise-induced hearing loss in arbitration of medicolegal aspects. We investigated the accuracy of multiple-frequency auditory steady-state responses (Mf-ASSRs) between subjects with sensorineural hearing loss (SNHL) with and without occupational noise exposure. DESIGN: Cross-sectional study. SETTING: Tertiary referral medical centre. METHODS: Pure-tone audiometry and Mf-ASSRs were recorded in 88 subjects (34 patients had occupational noise-induced hearing loss [NIHL], 36 patients had SNHL without noise exposure, and 18 volunteers were normal controls). MAIN OUTCOME MEASURES: Inter- and intragroup comparisons were made. A predicting equation was derived using multiple linear regression analysis. RESULTS: ASSRs and pure-tone thresholds (PTTs) showed a strong correlation for all subjects (r = .77 ≈ .94). The relationship is demonstrated by the equationThe differences between the ASSR and PTT were significantly higher for the NIHL group than for the subjects with non-noise-induced SNHL (p < .001). CONCLUSIONS: Mf-ASSR is a promising tool for objectively evaluating hearing thresholds. Predictive value may be lower in subjects with occupational hearing loss. Regardless of carrier frequencies, the severity of hearing loss affects the steady-state response. Moreover, the ASSR may assist in detecting noise-induced injury of the auditory pathway. A multiple linear regression equation to accurately predict thresholds was shown that takes into consideration all effect factors.

The protective effect of Rho-associated kinase inhibitor on aluminum-induced neurotoxicity in rat cortical neurons.

Aluminum (Al) is a neurotoxicant and is implicated in several neurodegenerative diseases, including Alzheimer's disease (AD). In AD brains, one of the pathological hallmarks is the extracellular deposition of senile plaques, which are mainly composed of aggregated amyloid-beta (Abeta). Endoproteolysis of the amyloid-beta precursor protein (AbetaPP) by the beta-secretase and the gamma-secretase generates Abeta. AbetaPP can also be cleaved by the alpha-secretase within the Abeta region, which releases a soluble fragment sAPPalpha and precludes the formation of Abeta. Al has been reported to increase the level of Abeta, promote Abeta aggregation, and increase Abeta neurotoxicity. In contrast, small G protein Rho and its effector, Rho-associated kinase (ROCK), are known to negatively regulate the amount of Abeta. Inhibition of the Rho-ROCK pathway may underlie the ability of nonsteroidal anti-inflammatory drugs and statins to reduce Abeta production. Whether the Rho-ROCK pathway is involved in Al-induced elevation and aggregation of Abeta is unknown. In the present study, cultured rat cortical neurons were treated with Al(malt)(3) in the absence or presence of ROCK inhibitor Y-27632. After the treatment of Al(malt)(3), the cell viability and the level of sAPPalpha were reduced, whereas the amyloid fibrils in the conditioned media were increased. Treatment with Y-27632 prevented these adverse effects of Al(malt)(3) and thus maintained neuronal survival. These results reveal that the activation of the Rho-ROCK signaling pathway was involved in Al-induced effects in terms of the cell viability, the production of sAPPalpha, and the formation of amyloid fibril, which provides a novel mechanism underlying Al-induced neurotoxicity.

Incidence of Creutzfeldt-Jakob disease in Taiwan: a prospective 10-year surveillance.

This study was performed to estimate the incidence of Creutzfeldt-Jakob Disease (CJD) in Taiwan from 1998 to 2007. Suspected cases of CJD were reported to the Taiwan Creutzfeldt-Jakob Disease Surveillance Unit, a nationwide, hospital-based case report system initiated since 1996 to prospectively conduct a CJD epidemiological study. Consecutive patients who met the diagnostic criteria recommended by the World Health Organization were enrolled. The clinical information of each suspected case was collected and case ascertainment was performed by an expert committee. A total of 123 sporadic CJD were identified without any iatrogenic or new variant CJD cases. The overall annual incidence rate (95% CI) was 0.55 (0.46-0.65) cases per million person-year. There was no statistically significant difference between the calendar year of disease onset (P = 0.97). The incidence rates were not significantly different between women and men (P = 0.63). Age was the main factor for the risk of CJD (P < 0.0001). Age-specific incidence rate increased after the age of 40 years with the peak being in the 70-79 years age group. Our data showed low annual incidence rate and high frequency of methionine homozygous prion protein genotype of sCJD in Taiwan. This report provided important epidemiological data on ethnic Chinese.

Longitudinal study of carbon monoxide intoxication by diffusion tensor imaging with neuropsychiatric correlation.

BACKGROUND: White matter damage is common after carbon monoxide (CO) intoxication, but in vivo follow-up studies about the mechanism of white matter damage are not possible in pathology series. Diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) can quantify diffusion parameters and volumetric changes in white matter that can be correlated with neuropsychological performances in longitudinal studies. METHODS: We examined 9 patients with CO intoxication using DTI, VBM and neuropsychologic tests at an average of 3 and 10 months after CO exposure. We used data from 18 age- and sex-matched controls for comparison. RESULTS: We found that cognitive recovery at 10 months after CO intoxication was not significant, although it was after 3 months. The neuropsychologic tests correlated better for the fibre tract of the semicentrum ovale and not the periventricular fibres. Diffusion measures suggest increases in fractional anisotropy, mean diffusivity and axial eigenvalues over time, while increases in radial eigenvalue were evident at 3 months compared with controls. Periventricular white matter atrophy was observed 10 months after CO intoxication. LIMITATIONS: Our study included few cases, and the interpretation of the putative changes on neuroimaging findings cannot be confirmed by histology. CONCLUSION: Our study showed that the evolution of white matter injury in CO encephalopathy occurred over time. Cognitive recovery was not evident in the follow-up period because of white matter injuries.

Measurement of the functional status of patients with different types of muscular dystrophy.

Muscular dystrophy (MD) comprises a group of diseases characterized by progressive muscle weakness that induces functional deterioration. Clinical management requires the use of a well-designed scale to measure patients' functional status. This study aimed to investigate the quality of the functional scales used to assess patients with different types of MD. The Brooke scale and the Vignos scale were used to grade arm and leg function, respectively. The Barthel Index was used to evaluate the function of daily living activity. We performed tests to assess the acceptability of these scales. The characteristics of the different types of MD are discussed. This was a multicenter study and included patients diagnosed with Duchenne muscular dystrophy (DMD) (classified as severely progressive MD), Becker muscular dystrophy (BMD), limb girdle muscular dystrophy (LGMD) and facioscapulohumeral muscular dystrophy (FSHD). BMD, LGMD, and FSHD were classified as slowly progressive MD. The results demonstrated that the Brooke scale was acceptable for grading arm function in DMD, but was unable to discriminate between differing levels of severity in slowly progressive MD. The floor effect was large for all types of slowly progressive MD (range, 20.0-61.9), and was especially high for BMD. The floor effect was also large for BMD (23.8%) and FSHD (50.0%) using the Vignos scale. Grades 6-8 of the Vignos scale were inapplicable because they included items involving the use of long leg braces for walking or standing, and some patients did not use long leg braces. In the Barthel Index, a ceiling effect was prominent for slowly progressive MD (58.9%), while a floor effect existed for DMD (17.9%). Among the slowly progressive MDs, FSHD patients had the best level of functioning; they had better leg function and their daily living activities were less affected than patients with other forms of slowly progressive MD. The results of this study demonstrate the acceptability of the different applications used for measuring functional status in patients with different types of MD. Some of the limitations of these measures as applied to MD should be carefully considered, especially in patients with slowly progressive MD. We suggest that these applications be used in combination with other measures, or that a complicated instrument capable of evaluating the various levels of functional status be used.

Damage of white matter tract correlated with neuropsychological deficits in carbon monoxide intoxication after hyperbaric oxygen therapy.

Carbon monoxide (CO) intoxication can result in cognitive deficits and demyelinating changes of the white matter (WM), for which hyperbaric-oxygen (HBO) treatment is considered effective in reducing neuropsychiatric symptoms. This study aimed to analyze cognitive functions and WM diffusion properties in CO intoxication after standard HBO treatment. Seventeen CO intoxicated patients were evaluated 4-6 months after HBO treatment. They also underwent diffusion tensor imaging (DTI) and cognitive assessment, and the results were compared with those from 34 age-matched controls. DTI was transformed into fractional anisotropy (FA) and mean diffusivity (MD) and assessed at every voxel level with tract-based spatial statistics across the brain. Correlation between reduced FA and increased MD with neuropsychological deficits were performed. Cognitive results showed that impairment in executive function, as well as verbal and visual memories, were most prominent. There were extensive areas of increased MD and decreased FA. Correlation analyses showed that memory retrieval, judgment, and verbal generation tasks were related to FA of the frontotemporal WM. MD showed weaker correlation with cognitive deficits. These data suggest that neurologic deficits and WM changes are detectable 4-6 months after HBO therapy. The correlation of WM diffusion with cognitive deficits also suggests that reduced connectivity between different cortical regions is a pathophysiologic mechanism.

Amyloid-beta interrupts the PI3K-Akt-mTOR signaling pathway that could be involved in brain-derived neurotrophic factor-induced Arc expression in rat cortical neurons.

The deposition of amyloid-beta (Abeta) contributes to the pathogenesis of Alzheimer's disease. Even at low levels, Abeta may interfere with various signaling cascades critical for the synaptic plasticity that underlies learning and memory. Brain-derived neurotrophic factor (BDNF) is well known to be capable of inducing the synthesis of activity-regulated cytoskeleton-associated protein (Arc), which plays a fundamental role in modulating synaptic plasticity. Our recent study has demonstrated that treatment of fibrillar Abeta at a nonlethal level was sufficient to impair BDNF-induced Arc expression in cultured rat cortical neurons. In this study, BDNF treatment alone induced the activation of the phosphatidylinositol 3-kinase-Akt-mammlian target of rapamycin (PI3K-Akt-mTOR) signaling pathway, the phosphorylation of eukaryotic initiation factor 4E binding protein (4EBP1) and p70 ribosomal S6 kinase (p70S6K), the dephosphorylation of eukaryotic elongation factor 2 (eEF2), and the expression of Arc. Interrupting the PI3K-Akt-mTOR signaling pathway by inhibitors prevented the effects of BDNF, indicating the involvement of this pathway in BDNF-induced 4EBP1 phosphorylation, p70S6K phosphorylation, eEF2 dephosphorylation, and Arc expression. Nonlethal Abeta pretreatment partially blocked these effects of BDNF. Double- immunofluorescent staining in rat cortical neurons further confirmed the coexistence of eEF2 dephosphorylation and Arc expression following BDNF treatment regardless of the presence of Abeta. These results reveal that, in cultured rat cortical neurons, Abeta interrupts the PI3K-Akt-mTOR signaling pathway that could be involved in BDNF-induced Arc expression. Moreover, this study also provides the first evidence that there is a close correlation between BDNF-induced eEF2 dephosphorylation and BDNF-induced Arc expression. (c) 2009 Wiley-Liss, Inc.

Functional changes on ascending auditory pathway in rats caused by germanium dioxide exposure: an electrophysiological study.

The semiconductor element, germanium (Ge), is essential for the manufacture of modern integrated circuits. Because of its anti-tumor and immunomodulative effects, Ge-containing compounds are also used as health-promoting ingredients in food. However, some histological studies have shown the toxic effects of Ge-containing compounds on various organs, including the central nervous system. Even now, the effect of germanium on auditory system function is not completely clear. To clarify this question, brainstem auditory evoked potentials (BAEPs) were applied to examine the effect of germanium dioxide (GeO(2)) on the ascending auditory pathway. Since the voltage-gated sodium channel is important to neuron activation and nerve conduction, the effect of GeO(2) on voltage-gated sodium channels was also examined. The result revealed GeO(2) elevated the BAEPs threshold dose-dependently. GeO(2) also prolonged latencies and interpeak latencies (IPLs) of BAEPs, but the amplitudes of suprathreshold intensities (90dB) did not show any obvious change. In addition, the results of whole cell patch clamp studies indicated GeO(2) reduced inward sodium current. These results suggest the toxic effect of GeO(2) on the conduction of the auditory system, and that inhibitory effect of GeO(2) on the voltage-gated sodium channels might play a role in GeO(2)-induced abnormal hearing loss.

Kennedy disease mimics amyotrophic lateral sclerosis: a case report.

Kennedy disease (KD) is an X-linked inherited motor neuron disease that is often accompanied by androgen insensitivity. Its estimated incidence in the US is approximately 1 case in 40,000 men. KD has also been reported in individuals of different racial backgrounds, especially in Japanese but the prevalence rate in Taiwan has not been fully investigated. Here we report a case of KD definitely diagnosed by abnormal expansion of a polymorphic tandem cytosine-adenine-guanine (CAG) triplet repeat in the first exon of the androgen receptor gene. The direct genotyping from polymerase chain reaction product is subsequently performed utilizing capillary electrophoresis. The patient's neurological conditions mimic amyotrophic lateral sclerosis (ALS). Since these two diseases have different etiologies and prognosis, it reminds us the necessity to rule out KD in face with a suspected male case of ALS.