Jin-Bor Chen

QTc prolongation indicates a poor prognosis in patients with organophosphate poisoning

This study reviewed emergency department electrocardiograms of 223 patients with organophosphate poisoning from January 1982 to June 1994: 97 (43.5%) had QTc prolongation and were placed in group A; 126 patients without QTc prolongation were designated as group B. Compared with group B, group A patients had a higher mortality (19.6% v 4.8%, P < .001) and a higher incidence of respiratory failure (56.7% v 20.6%, P < .001). Serum cholinesterase levels were determined in the 223 patients: 92 (41.3%) were classified as severe poisoning. 32 (14.3%) as moderate, 41 (18.1%) as mild, and 58 (25.7%) as very mild. The severe group had a high incidence of QTc prolongation (P < .001), a high incidence of respiratory failure (P < 0.001), and a higher mortality rate (P < 0.001) than the other groups. Of the QTc prolongation patients, 59.8% (55/92) had a high incidence of respiratory failure (78.2% v 35.1%, P < .0001) and a higher mortality rate (29.1% v 8.1%, P < 0.05) compared with 40.2% (37/92) of the patients without QTc prolongation in the severe group. In conclusion, a complete electrocardiogram at the emergency department is important and of prognostic value.

Hyponatremia in the emergency department.

Hyponatremia is a clinical manifestation of a wide variety of diseases, some of which have high mortality rates. To assess the prevalence, cause, and prognosis of hyponatremia encountered in the emergency department, we conducted a prospective study at a major hospital in southern Taiwan. We included all adult internal medicine patients treated in the emergency department during a 2-month period. Hyponatremia was defined as a serum sodium level below 134 mEq/L, and cases patients were followed till being discharged. Among the 3,784 patients included, 166 case patients were identified. Most (65%) case patients were hypovolemic, and the overall mortality rate was 17.9%. The mortality rate increased as the sodium level decreased, but was not related to gender, age, cause, or serum potassium level. When 21 hyperglycemic patients whose serum sodium levels went beyond 134 mEq/L after the adjustment for blood sugar levels were excluded, the prevalence of true hyponatremia was 3.83%. The most common underlying diseases were those of the gastrointestinal system. It is concluded that hyponatremia is a common condition encountered in the emergency department. The mortality is correlated with the serum sodium level, and adjustment of the level is required in hyperglycemic patients to make a correct diagnosis. Unlike the cases in some other clinical settings, almost all cases of hyponatremia encountered in the emergency department were not iatrogenic and had recognizable underlying diseases. Therefore, more effort is generally required to identify the cause of hyponatremia cases in the emergency department.

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.

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.

Sequence-based polymorphisms in the mitochondrial D-loop and potential SNP predictors for chronic dialysis.

Background The mitochondrial (mt) displacement loop (D-loop) is known to accumulate structural alterations and mutations. The aim of this study was to investigate the prevalence of single nucleotide polymorphisms (SNPs) within the D-loop among chronic dialysis patients and healthy controls. Methodology and Principal Findings We enrolled 193 chronic dialysis patients and 704 healthy controls. SNPs were identified by large scale D-loop sequencing and bioinformatic analysis. Chronic dialysis patients had lower body mass index, blood thiols, and cholesterol levels than controls. A total of 77 SNPs matched with the positions in reference of the Revised Cambridge Reference Sequence (CRS) were found in the study population. Chronic dialysis patients had a significantly higher incidence of 9 SNPs compared to controls. These include SNP5 (16108Y), SNP17 (16172Y), SNP21 (16223Y), SNP34 (16274R), SNP35 (16278Y), SNP55 (16463R), SNP56 (16519Y), SNP64 (185R), and SNP65 (189R) in D-loop of CRS. Among these SNPs with genotypes, SNP55-G, SNP56-C, and SNP64-A were 4.78, 1.47, and 5.15 times more frequent in dialysis patients compared to controls (P<0.05), respectively. When adjusting the covariates of demographics and comorbidities, SNP64-A was 5.13 times more frequent in dialysis patients compared to controls (P<0.01). Furthermore, SNP64-A was found to be 35.80, 3.48, 4.69, 5,55, and 4.67 times higher in female patients and in patients without diabetes, coronary artery disease, smoking, and hypertension in an independent significance manner (P<0.05), respectively. In patients older than 50 years or with hypertension, SNP34-A and SNP17-C were found to be 7.97 and 3.71 times more frequent (P<0.05) compared to patients younger than 50 years or those without hypertension, respectively. Conclusions and Significance The results of large-scale sequencing suggest that specific SNPs in the mtDNA D-loop are significantly associated with chronic dialysis. These SNPs can be considered as potential predictors for chronic dialysis.

Mitochondrial DNA copy number correlates with oxidative stress and predicts mortality in nondiabetic hemodialysis patients

BACKGROUNDnOxidative stress is highly prevalent in hemodialysis patients and may contribute to atherosclerosis and mortality. The copy number of mitochondrial DNA (mtDNA) is affected by oxidative stress in blood circulation. This study aimed to test whether mtDNA copy number correlates with oxidative stress and predicts all-cause mortality in nondiabetic hemodialysis patients.nnnMETHODSnNinety-five nondiabetic hemodialysis patients and 95 healthy subjects were enrolled. Plasma thiobarbituric acid-reactive substances (TBARS) and plasma free thiol were used as indicators of oxidative stress and antioxidant defense, respectively. Mitochondrial DNA copy number in peripheral blood leukocytes was measured by determining relative amounts of mtDNA to nuclear DNA by quantitative real-time PCR. All-cause mortality of hemodialysis patient was recorded during a follow-up of 3 years.nnnRESULTSnNondiabetic hemodialysis patients showed higher TBARS levels, lower free thiol levels and higher mtDNA copy numbers compared with normal control subjects. The plasma TBARS level was a significant factor correlating positively to the mtDNA copy number (p=0.024). Patients with a mtDNA copy number higher than the median had a higher all-cause mortality than patients with a lower mtDNA copy number (17.0% vs. 4.2%; log-rank test: p=0.038). A 1-log increase in mtDNA copy number was independently related to an increase in the risk for mortality (hazard ratio 21.360; 95% confidence interval, 1.298-351.572).nnnCONCLUSIONSnNondiabetic hemodialysis patients had higher oxidative stress and mtDNA copy numbers than healthy subjects. The mtDNA copy number correlates with oxidative stress and predicts mortality in nondiabetic hemodialysis patients.

Tissue-specific differences in mitochondrial DNA content in type 2 diabetes

BACKGROUNDnTo investigate whether the effect of hyperglycemia on mitochondrial DNA (mtDNA) content is tissue-specific.nnnMETHODnWe compared the mtDNA contents in leg muscle, blood vessel, and peripheral leucocytes in seventeen patients with type 2 diabetes (T2DM) with those of seven controls. We measured 8-hydroxydeoxyguanosine (8-OHdG) expression in the muscles and thiobarbituric acid reactive substance (TBARS) in sera to evaluate oxidative stress. Immunohistochemical detection of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1-α), mitochondrial transcription factor A (Tfam), and apoptosis were performed in the muscle tissue.nnnRESULTSnThe mtDNA copy number was highest in muscle tissue, followed by blood vessel tissue, and lowest in leucocytes in both the diabetic and control subjects. The diabetic patients had less mtDNA content in the muscle than the controls (2.86±0.33 vs. 3.20±0.14, P=0.025), but more mtDNA content in the leucocytes (2.25±0.26 vs. 1.98±0.06, P=0.04). In both groups, there was a positive correlation between muscle tissue mtDNA content and the expression of 8-OHdG. Patients with T2DM had significantly increased 8-OHdG and TUNEL labeling index and non-significant increases in the expression of PGC1-α and Tfam.nnnCONCLUSIONnOxidative stress stimulates mitochondrial biogenesis but induces a greater degree of apoptosis in diabetic patients, resulting in a decrease in muscle tissue mtDNA content.

Mitochondrial transfer from Wharton's jelly-derived mesenchymal stem cells to mitochondria-defective cells recaptures impaired mitochondrial function

Adult mesenchymal stem cell (MSC)-conducted mitochondrial transfer has been recently shown to rescue cellular bioenergetics and prevent cell death caused by mitochondrial dysfunction. Whartons jelly-derived MSCs (WJMSCs) harvested from postpartum umbilical cords are an accessible and abundant source of stem cells. This study aimed to determine the capability of WJMSCs to transfer their own mitochondria and rescue impaired oxidative phosphorylation (OXPHOS) and bioenergetics caused by mitochondrial DNA defects. To do this, WJMSCs were co-cultured with mitochondrial DNA (mtDNA)-depleted ρ(0) cells and the recapture of mitochondrial function was evaluated. WJMSCs were shown to be capable of transferring their own mitochondria into ρ(0) cells and underwent interorganellar mixture within these cells. Permissive culture media (BrdU-containing and pyruvate- and uridine-free) sieved out a survival cell population from the co-cultured WJMSCs (BrdU-sensitive) and ρ(0) cells (pyruvate/uridine-free). The survival cells had mtDNA identical to that of WJMSCs, whereas they expressed cellular markers identical to that of ρ(0) cells. Importantly, these ρ(0)-plus -WJMSC-mtDNA (ρ(+W)) cells recovered the expression of mtDNA-encoded proteins and exhibited functional oxygen consumption and respiratory control, as well as the activity of electron transport chain (ETC) complexes I, II, III and IV. In addition, ETC complex V-inhibitor-sensitive ATP production and metabolic shifting were also recovered. Furthermore, cellular behaviors including attachment-free proliferation, aerobic viability and OXPHOS-reliant cellular motility were also regained after mitochondrial transfer by WJMSCs. The therapeutic effect of WJMSCs-derived mitochondrial transfer was able to stably sustain for at least 45 passages. In conclusion, this study suggests that WJMSCs may serve as a potential therapeutic strategy for diseases linked to mitochondrial dysfunction through the donation of healthy mitochondria to cells with genetic mitochondrial defects.

The Creation of Cybrids Harboring Mitochondrial Haplogroups in the Taiwanese Population of Ethnic Chinese Background: An Extensive In Vitro Tool for the Study of Mitochondrial Genomic Variations

Mitochondrial DNA (mtDNA) haplogroups may contribute to the development of aging-related diseases. A reliable in vitro cellular system for investigating the physiologic significance of mtDNA haplogroups is essential. This study aims to construct and characterize a series of cybrid cell lines harboring variant mtDNA haplogroups collected from healthy Taiwanese volunteers. Cybrid cells harboring different mtDNA haplogroups like B4a, B4b, B4c, B4d, B5, R, F1a, F2, D4e, D4a, D5b, D5a, E, M8, C, and N9a were prepared. Luminex 1000 and full-length mtDNA sequencing were used to confirm that mtDNA haplogroups of transmitochondrial cybrids were identical to their original donors. Cybrid B4b had a significantly lower oxygen consumption rate and higher mitochondrial membrane potential compared to F1a, B5, D5a, D4a, and N9a but had more susceptibility to H2O2-induced oxidative stress than cybrid F1a, D4a, and N9a. Cybrid N9a had better oxygen consumption and H2O2-challenged viability compared to B4b, F1a, B5, D5a, and D4a. A series of cybrid cells harboring the main haplogroups of the Taiwanese population with ethnic Chinese background has been developed in vitro. With this mtDNA haplogroup population, the underlying mechanisms of aging-related diseases may be better understood, and therapeutic interventions can be accelerated.

Predictive Factors and Long-Term Outcome of Respiratory Failure after Guillain-Barré Syndrome

Objective:To analyze predictive factors and long-term recovery in patients with Guillain-Barré syndrome (GBS) who are in need of mechanical ventilation. Methods:In this 15-year retrospective study, 77 adult patients were identified with GBS. A comparison was made between the clinical data from patients who required mechanical ventilation and those who did not. Furthermore, the therapeutic outcomes of those 25 patients in need of mechanical ventilation during hospitalization at 1 year were determined using a modified Barthel index. A score below 12 was defined as a poor outcome, whereas a score of 12 or more was good. Results:The study revealed 32% of patients (25/77) in need of respiratory support during hospitalization. At a follow-up of 1 year among the 25 ventilated patients, 7 patients (28%) had normal or minor signs and symptoms, 6 had unassisted gait, 3 had assisted gait, 6 were wheelchair- or bed-bound, and 3 died. The cause of death was septicemia with septic shock in all 3 cases. Factors that predict respiratory failure in the study GBS patients were disability grade on admission and areflexia. Those ventilated patients who had low maximal inspiratory pressure (PImax) (<14.5 cmH2O) and maximal expiratory pressure (PEmax) (<13.5 cmH2O) values at the time of intubation and the presence of complications after mechanical ventilation inevitably had worse outcomes than those who had not. Conclusion:If low values of PImax and PEmax at intubation were detected, aggressive respiratory management, which might include tracheostomy to allow more efficient bronchial clearing, and prevention of complications caused by prolonged course of mechanical ventilation are essential to maximize the potential for survival.