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.

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.

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.

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.

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.

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.

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.

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.

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.

Statin-induced heme oxygenase-1 increases NF-kappaB activation and oxygen radical production in cultured neuronal cells exposed to lipopolysaccharide.

With potentially neuroprotective properties, heme oxygenase-1 (HO-1) has been suggested to be the main mediator of cholesterol-independent anti-inflammatory and antioxidant actions of statins. However, we had demonstrated that simvastatin-induced HO-1 increased apoptosis of Neuro 2A cells in glucose deprivation, and iron production from HO-1 activity may be responsible for the toxicity. This study was designed to explore the effect of simvastatin-induced HO-1 on cultured Neuro 2A and C6 cells exposed to lipopolysaccharide (LPS). We found that the HO-1 upregulation was significantly associated with increased nuclear factor kappa B (NF-kappaB) activation, manifested as IkappaBalpha phosphorylation and p65 nuclear translocation, as well as increased production of superoxides. Inhibition of the induced HO-1 by zinc protoporphyrin reduced the increased NF-kappaB activation and superoxides production. RNA interference with HO-1 siRNA reduced the expression of HO-1 transcripts and protein as well as oxygen radical production. Addition of the iron chelator desferrioxamine to reduce the accumulation of ferric iron from heme by HO-1 resulted in blockade of the aggravated oxygen radical production. There was no significant effect on production of oxygen radicals under these conditions in the presence of a CO donor (RuCO) or a CO scavenger (hemoglobin). In addition, the viable cells were significantly decreased in 48 h in those cells receiving simvastatin pretreatment plus LPS compared to those in control or exposed to simvastatin or LPS alone. This study revealed that simvastatin-induced HO-1 led to increased NF-kappaB activation and superoxides production in the neuronal cells when exposed to LPS, and iron production may play a role in such a response.

Simvastatin-induced heme oxygenase-1 increases apoptosis of Neuro 2A cells in response to glucose deprivation.

Heme oxygenase-1 (HO-1) has been suggested as an important mediator of the cholesterol-independent cytoprotection actions of statins, which may be of benefit for the treatment of degenerative neurological diseases and for reduction of infarct volume after cerebral ischemia. Overexpression of HO-1, however, has dual effects under oxidative stress, and the release of ferric iron from heme under these conditions may result in detrimental rather than cytoprotective effects. This study was designed to investigate the effect of simvastatin-induced HO-1 on Neuro 2A cells in response to glucose deprivation. We demonstrated that simvastatin induced a dose- and time-dependent upregulation of HO-1 protein expression in Neuro 2A cells. The induction of HO-1 after simvastatin treatment was mediated by nuclear factor erythroid 2-related factor 2 (Nrf2), which was expressed by Western blots of nuclear fractions and retarded complex formation in the electrophoretic mobility shift assay reaction. In addition, simvastatin activated the extracellular signal-regulated kinase and p38, but not the phosphorylation of c-Jun N-terminal kinase and Akt. Glucose deprivation in the cells pretreated with simvastatin induced more HO-1 expression, and the transcript could be decreased by small interfering RNA for Nrf2. This upregulation of HO-1 was significantly associated with increased apoptosis, manifested as expression at the protein level of 17-kDa cleaved caspase-3 and increased percentage of apoptotic cells shown by flow cytometry. The increased cleaved caspase-3 expression and percentage of apoptotic cells was significantly reduced by the HO inhibitor zinc protoporphyrin. Addition of the iron chelator desferrioxamine also resulted in blockade of the aggravated apoptosis, which implies that iron production from HO-1 activity may play an important role in the increased apoptosis in response to glucose deprivation in neuronal cells pretreated with simvastatin.

Crossed cheiro-oral syndrome.

OBJECTIVES: Cheiro-oral syndrome is characterized by sensory impairment confined to perioral area and ipsilateral fingers/hand. It results from an involvement of the ascending sensory tracts above the pons. However, a crossed pattern of perioral and acral paresthesia was rarely reported before. PATIENTS AND METHODS: This study reports the neuroanatomic relationship, course and clinical significance of perioral and contralateral acral paresthesia in four patients. We term it the crossed cheiro-oral syndrome. RESULTS: All patients had lateral or dorsolateral medullary infarctions that were ipsilateral to their perioral paresthesia. The contributory origin is considered a diagonal lesion involving the par oralis fibers within the descending trigeminal sensory tract and acral portion of the lateral spinothalamic tract at the lateral portion of medulla oblongata. Despite of a restricted sensory disturbance at initial, progressive neurological disability terminated to Wallenberg's syndrome ensued in three patients and disabling deficits persisted in two of them. CONCLUSION: The crossed cheiro-oral syndrome seems a mild form of Wallenberg's syndrome. Therefore, it predicts medullary involvement and is also a warning sign for progression.

Decreased muscular radionuclide uptake in Tc-99m MIBI scintigraphy during paralytic phase of thyrotoxic periodic paralysis.

The underlying pathophysiology of thyrotoxic periodic paralysis (TPP) is still obscure. From histologic surveys, vacuole formation and abundant mitochondrial abnormalities ranged from swelling, matrical pallor, pleomorphism, and reduced cristae were often disclosed in the muscle fibers during paralytic periods. In a 47-year-old man experiencing 2 episodes of transient paralysis, hyperthyroidism with TPP was diagnosed. During the acute paralytic phase, a significant reduction of radionucleotide uptake in the quadriceps on Tc-99m sestamibi scintigraphy was found, aside from the previous morphologic findings, that it further suggests impaired mitochondrial integrity and cellular viability in TPP.

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.

Uncoupling of protein C and antithrombin III activity in cerebral ischemia patients associated with cutis marmorata.

PURPOSE: Cutis marmorata is a cutaneous livedoid disorder which can be differentiated from livedo reticularis in both clinical and pathological presentations. Unlike Sneddon syndrome, a detailed immunocoagulation profile has not yet been delineated for cutis marmorata in patients with cerebral ischemia. METHODS: To analyze the immunocoagulation profile in cutis marmorata patients associated with cerebral ischemia (CMCI) in a series of 135 cerebral ischemia patients. RESULTS: A total of 32 patients were found to have cutis marmorata. The blood protein C activity, protein S activity, antithrombin III activity, platelet count, fibrinogen and frequency of abnormal antiphospholipid antibody level were similar among 32 CMCI patients, 103 cerebral ischemia patients without cutis marmorata, and 35 healthy subjects. However, uncoupling of protein C and anti-thrombin III was observed in CMCI patients. Serum antinuclear antibody and Venereal Disease Research Laboratory were not detected in these patients. CONCLUSION: Cutis marmorata is not uncommon in our ischemic stroke patient population, and is characterized by uncoupling of protein C and antithrombin III with altered thrombin hemostasis. Our findings raise the need for a careful cutaneous examination in patients with ischemic stroke. Abnormal immunocoagulating profile should alert physicians to the risk for cerebral ischemia even in the absence of other cardiovascular risk factors.

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.

New molecular insights into cellular survival and stress responses: neuroprotective role of cellular prion protein (PrPC).

Knowledge of the physiological function of cellular prion protein has been acquired from prion diseases such as Creutzfeldt-Jakob disease, as well as PRNP knock out and transgenic mice. Recent progress in neurobiology has further delineated the neuroprotective role played by cellular prion protein. In this paper, we review the role of cellular prion protein in cell survival including its antiapoptotic effect on Bax-mediated cell death and its responses to various environmental stresses including oxidative stress, and ischemia. Finally, we discuss the significance of cellular prion protein in different neurodegenerative diseases and the possible development of future therapies.

Loss of small fibers in entrapment neuropathy and their regeneration after surgical decompression in a rat model.

The study was carried out to investigate the loss of small fibers during entrapment neuropathy and their regeneration after surgical decompression. Entrapment neuropathy was mimicked in a rat model by wrapping the right sciatic nerve of Sprague-Dawley rats with a silastic tube of 1.3 mm inner diameter. A sham operation was performed on the left side. Additional naive rats were used as controls. In the subgroup of rats that received surgical decompression, removal of the tube was performed six months later. Intra-epidermal nerve fiber density (IENFD) was quantified by measuring protein gene product 9.5-immunoreactive epidermal nerve fibers in bilateral hindpaws. The results showed progressive reduction of IENFD after 1, 3, and 6 months of nerve entrapment (e1m, e3m and e6m): naive rats, 20.04+/-2.26 (e1m), 19.39+/-2.38 (e3m), 20.45+/-2.40 (e6m); right side with entrapment, 12.12+/-2.12 (e1m), 6.27+/-1.02 (e3m), 1.83+/-0.48 (e6m); left side after sham procedure, 13.72+/-2.20 (e1m), 8.59+/-1.37 (e3m), 4.56+/-1.07 (e6m) fibers/mm. Small fiber deficit was present both on the side with the entrapment and the contralateral side that had undergone the sham procedure. Increased IENFD was found at 1 and 3 months post-decompression (d1m and d3m), but failed to return to that of the naive rats: naive rats, 20.38+/-2.24 (d1m), 18.94+/-2.24 (d3m); entrapment, 7.00+/-1.14 (d1m), 6.97+/-1.40 (d3m); sham, 6.41+/-1.16 (d1m), 9.92+/-1.64 (d3m) fibers/mm. These findings demonstrate progressive degeneration of small fibers during entrapment neuropathy and partial restoration of innervation after decompression. The results also imply that, in addition to the contralateral side, naive controls are mandatory in the study of small fiber loss in entrapment neuropathy.

The relation between plasma homocysteine level and cardiovascular risk factors in cerebral ischemia.

PURPOSE: Hyperhomocysteinemia (HHcy) is associated with a higher risk of cerebral ischemia and other vascular thrombosis. Homocysteine is greatly influenced by a broad spectrum of physiological and pathological conditions but the confounding factor for HHcy is unknown in our population, especially in normocreatininemic individuals. It is our aim in this study to elucidate the relation between homocysteine and cardiovascular risk factors, and also describe the distribution of plasma homocysteine level in cerebral ischemia patients with normal serum creatinine level. METHODS: A retrospective study was conducted to understand the frequency of HHcy in cerebral ischemia patients, and the confounding cardiovascular risk factors in HHcy. Patients were classified into two groups by their plasma homocysteine levels; group I patients were those whose level was > or = 12 microM/L whereas group II < 12 microM/L. RESULTS: A total of 218 patients were enrolled. Their plasma homocysteine level ranged from 3.57 to 46.37 microM/L (mean: 10.01 +/- 5.03 microM/L). Group I included 45 patients whereas group II 173 patients. The frequency of hypertension, diabetes mellitus and cardiac disease, as well as age, aminotransferases, total cholesterol, triglyceride, albumin, hematocrit, hemoglobin and leucocyte count did not differ between group I and II patients, except serum creatinine level was higher in group I patients (p < 0.01). Serum creatinine level correlated directly to and was an independent predictor for the plasma homocysteine level. CONCLUSIONS: HHcy is common in our cerebral ischemia patients. Since renal function is a determinant for HHcy even in normocreatininemic patients, as a cardiovascular risk factor which detriments the renal function, it should be regularly monitored as HHcy is amenable for treatment.