Yao-Chung Chuang

Effects of Long-Term Antiepileptic Drug Monotherapy on Vascular Risk Factors and Atherosclerosis.

Purpose:  Long‐term therapy with antiepileptic drugs (AEDs) has been associated with metabolic consequences that lead to an increase in risk of atherosclerosis in patients with epilepsy. We compared the long‐term effects of monotherapy using different categories of AEDs on markers of vascular risk and the atherosclerotic process.

Resveratrol Partially Prevents Rotenone-Induced Neurotoxicity in Dopaminergic SH-SY5Y Cells through Induction of Heme Oxygenase-1 Dependent Autophagy

Parkinson disease (PD) is a complex neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons. Mitochondrial dysfunction, oxidative stress or protein misfolding and aggregation may underlie this process. Autophagy is an intracellular catabolic mechanism responsible for protein degradation and recycling of damaged proteins and cytoplasmic organelles. Autophagic dysfunction may hasten the progression of neuronal degeneration. In this study, resveratrol promoted autophagic flux and protected dopaminergic neurons against rotenone-induced apoptosis. In an in vivo PD model, rotenone induced loss of dopaminergic neurons, increased oxidation of mitochondrial proteins and promoted autophagic vesicle development in brain tissue. The natural phytoalexin resveratrol prevented rotenone-induced neuronal apoptosis in vitro, and this pro-survival effect was abolished by an autophagic inhibitor. Although both rotenone and resveratrol promoted LC3-II accumulation, autophagic flux was inhibited by rotenone and augmented by resveratrol. Further, rotenone reduced heme oxygenase-1 (HO-1) expression, whereas resveratrol increased HO-1 expression. Pharmacological inhibition of HO-1 abolished resveratrol-mediated autophagy and neuroprotection. Notably, the effects of a pharmacological inducer of HO-1 were similar to those of resveratrol, and protected against rotenone-induced cell death in an autophagy-dependent manner, validating the hypothesis of HO-1 dependent autophagy in preventing neuronal death in the in vitro PD model. Collectively, our findings suggest that resveratrol induces HO-1 expression and prevents dopaminergic cell death by regulating autophagic flux; thus protecting against rotenone-induced neuronal apoptosis.

Long-term antiepileptic drug therapy contributes to the acceleration of atherosclerosis

Purpose:  Long‐term antiepileptic drug (AED) therapy has been associated with an increase in risk of atherosclerosis. At issue is whether this risk is related to the duration of AED therapy. We evaluated the hypothesis that the cumulative effect of long‐term exposure to AEDs plays a pivotal role in the pathogenesis of atherosclerosis in patients with epilepsy.

The prognostic factors of adult gram-negative bacillary meningitis.

Seventy-seven patients with Gram-negative bacillary meningitis (GNBM), 57 males and 20 females, aged 17-86 years, were identified at Kaohsiung Chang Gung Memorial Hospital, over an 11-year period. Fifty-four infections were community-acquired, and 23 were nosocomial; 49 were spontaneous and 28 occurred after head surgery or neurosurgery. The organisms most frequently involved were Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, and Acinetobacter. Rarer pathogens included Citrobacter species, Serratia marcescens, Enterobacter cloacae, and Proteus mirabilis. All patients who did not receive appropriate antibiotic therapy died. The mortality in those treated with appropriate antibiotics was 28%. Other statistically significant prognostic factors included septic shock, initial level of consciousness, hyperosmolar hyperglycemic nonketotic coma, disseminated intravascular coagulation, high cerebrospinal fluid lactate levels and leucocytosis. In the multiple logistic regression analysis, only appropriate antimicrobial therapy and septic shock were strongly associated with mortality even after adjusting for other potentially confounding factors. Despite the high mortality, management can be improved by early diagnosis, early use of appropriate antibiotics, and correction of underlying and associated medical derangement.

Gram-negative bacillary meningitis in adult post-neurosurgical patients

BACKGROUND To assess the clinical features and therapeutic outcomes of gram-negative bacillary meningitis (GNBM) in adult postneurosurgical patients. METHODS Thirty adult patients with GNBM were included in this study. Their clinical features, laboratory data, prognostic factors, and therapeutic outcome were analyzed. The patients were 22 males and 8 females, aged 17-72 years. Seven had community-acquired infections and 23 had nosocomial infections. Two patients were associated with brain abscess. RESULTS The pathogens found in the 30 GNBM patients were Pseudomonas aeruginosa, Klebsiella species, Escherichia coli, Acinetobacter baumannii, and some rare pathogens including Citrobacter freundii, Serratia marcescens, Enterobacter cloacae, and Proteus mirabilis. Among these 30 patients, 8 patients with third-generation cephalosporin-resistant GNBM were identified since 1994; all infections were nosocomially acquired. Appropriate antibiotics were given to 22 patients. Eight patients did not receive appropriate antibiotic therapy. All eight died. The mortality rate in those treated with appropriate antibiotics was 14%. CONCLUSIONS There has been an increase of GNBM in postneurosurgical patients in recent years. In addition, the emergence of strains resistant to third-generation cephalosporins in this specific group of patients has also been noted in recent years, and has become a great therapeutic challenge. We noted many prognostic factors in postneurosurgical patients in this study; however, appropriate antibiotic therapy and initial consciousness level are the most significant ones. Therefore, in cases of postneurosurgical patients with nosocomially acquired GNBM, the possibility of third-generation cephalosporin resistance should be strongly suspected. Early initiation of appropriate antibiotic therapy is needed in this potentially fatal disease.

Post-neurosurgical nosocomial bacterial meningitis in adults: microbiology, clinical features, and outcomes

The clinical data of 62 adult patients who suffered post-neurosurgical nosocomial bacterial meningitis, retrospectively collected over a 16-year period, were studied. Cases were divided into two groups based on the date of presentation, the first period being 1986-1993 and the second 1994-2001. Fever and progressive consciousness disturbance were the most consistent clinical features - signs that may also be attributed to other postoperative neurosurgical problems. The common pathogens included Staphylococcus aureus, coagulase negative Staphylococcus, Pseudomonas aeruginosa, Escherichia coli, and Acinetobacter baumannii. An increase in polymicrobial infections and multi-antibiotic resistance during the second period was identified. In the first half of the study, mortality was 22%, and in the second half 36%. Adult post-neurosurgical nosocomial bacterial meningitis has become an important clinical problem. The choice of appropriate empirical antibiotics is challenging and must be guided by an awareness of the relative frequency of various pathogens and the increasing incidence of resistant strains. Although high mortality rates may, in part, be related to the primary brain pathology, early diagnosis and the timely use of antibiotics based on antimicrobial susceptibility testing are essential for survival.

Upregulation of nitric oxide synthase II contributes to apoptotic cell death in the hippocampal CA3 subfield via a cytochrome c/caspase-3 signaling cascade following induction of experimental temporal lobe status epilepticus in the rat

Status epilepticus results in preferential neuronal cell loss in the hippocampus. We evaluated the hypothesis that the repertoire of intracellular events in the vulnerable hippocampal CA3 subfield after induction of experimental temporal lobe status epilepticus entails upregulation of nitric oxide synthase II (NOS II), followed by the release of mitochondrial cytochrome c that triggers the cytosolic caspase-3 cascade, leading to apoptotic cell death. In Sprague-Dawley rats, significant and temporally correlated upregulation of NOS II (3-24h), but not NOS I or II expression, enhanced cytosolic translocation of cytochrome c (days 1 and 3), augmented activated caspase-3 in cytosol (days 1, 3 and 7) and DNA fragmentation (days 1, 3 and 7) was detected bilaterally in the hippocampal CA3 subfield after elicitation of sustained seizure activity by microinjection of kainic acid into the unilateral CA3 subfield. Application bilaterally into the hippocampal CA3 subfield of a selective NOS II inhibitor, S-methylisothiourea, significantly blunted these apoptotic events; a selective NOS I inhibitor, N(omega)-propyl-l-arginine or a potent NOS III inhibitor, N(5)-(1-iminoethyl)-l-ornithine was ineffective. We conclude that upregulation of NOS II contributes to apoptotic cell death in the hippocampal CA3 subfield via a cytochrome c/caspase-3 signaling cascade following the induction of experimental temporal lobe status epilepticus.

Mitochondrial DNA Coding and Control Region Variants as Genetic Risk Factors for Type 2 Diabetes

Both the coding and control regions of mitochondrial DNA (mtDNA) play roles in the generation of diabetes; however, no studies have thoroughly reported on the combined diabetogenic effects of variants in the two regions. We determined the mitochondrial haplogroup and the mtDNA sequence of the control region in 859 subjects with diabetes and 1,151 normoglycemic control subjects. Full-length mtDNA sequences were conducted in 40 subjects harboring specific diabetes-related haplogroups. Multivariate logistic regression analysis with adjustment for age, sex, and BMI revealed that subjects harboring the mitochondrial haplogroup B4 have significant association with diabetes (DM) (odds ratio [OR], 1.54 [95% CI 1.18–2.02]; P < 0.001), whereas subjects harboring D4 have borderline resistance against DM generation (0.68 [0.49–0.94]; P = 0.02). Upon further study, we identified an mtDNA composite group susceptible to DM generation consisting of a 10398A allele at the coding region and a polycytosine variant at nucleotide pair 16184–16193 of the control region, as well as a resistant group consisting of C5178A, A10398G, and T152C variants. The OR for susceptible group is 1.31 (95% CI 1.04–1.67; P = 0.024) and for the resistant group is 0.48 (0.31–0.75; P = 0.001). Our study found that mtDNA variants in the coding and control regions can have combined effects influencing diabetes generation.

Changing Epidemiology of Adult Bacterial Meningitis in Southern Taiwan: A Hospital-Based Study

Background:Many factors may influence the epidemiologic trend of adult bacterial meningitis (ABM). The objective of this study was to analyze recent epidemiologic trends of ABM in order to provide a better therapeutic strategy.Materials and Methods:The clinical features, laboratory data, and therapeutic outcomes of 181 ABM cases collected in the last 6.5 years (July 1999–December 2005) were analyzed. The results were compared with those of our previous study (202 cases, January 1986–June 1999).Results:The 181 cases consisted of 130 men (age range: 18–82 years) and 51 women (age range: 18–78 years). Monomicrobial infection and mixed infection were found in 165 cases and 16 cases, respectively. A preceding postneurosurgical state was noted in 56.9% (103/181) of cases. Despite a decrease in incidence, Klebsiella pneumoniae (25.5%, 42/165) was still the most common pathogen. A marked increase of Acinetobacter meningitis (11.5%, 19/165) was noted, which replaced Pseudomonas meningitis as the second most common Gram-negative pathogen in ABM. A marked increase in staphylococcal infection, accounting for 23% (38/165) of all cases, was also noted, of which 76% (29/38) were methicillin-resistant strains. The therapeutic result showed a mortality rate of 30.3% (55/181). Significant prognostic factors included septic shock and age at infection.Conclusions:This study revealed a change in the epidemiologic trend of ABM, with an increase in the number of patients with a postneurosurgical state and a rising incidence of Acinetobacter and staphylococcal infections. Clinicians should pay greater attention to these changes, which may affect their management of ABM.

Factors predictive of outcome in posttraumatic seizures.

BACKGROUND Seizures are important neurologic complications of traumatic brain injury (TBI). There is a need for better delineation of potential prognostic factors and outcomes in patients with posttraumatic seizures (PTS) who could receive treatment when brought to the hospital. METHODS In this 10-year retrospective study, 170 adult patients with PTS were enrolled in this study. The degree of seizure control was analyzed using a Seizure Frequency Scoring System, which classified them into excellent and nonexcellent outcomes. RESULTS There were 170 patients with acute symptomatic seizure enrolled in this study, 106 of whom had early PTS, whereas 64 had late PTS. Of the 106 early PTS, 58% (61 of 106) occurred within 24 hours of trauma. Risk factors for developing nonexcellent outcome included patients who undergo surgical intervention and presence of late-provoked seizures during the acute phase of TBI. CONCLUSIONS Seizures are an important neurologic complication of TBI. Regarding the potentially side effects of antiepileptic drugs, antiepileptic therapy should be carefully administrated in those nonexcellent outcome patients.