A new potential therapeutic approach for ALS: A case report with NGS analysis.

RATIONALE: Amyotrophic lateral sclerosis (ALS) poses a significant clinical challenge due to its rapid progression and limited treatment options, often leading to deadly outcomes. Looking for effective therapeutic interventions is critical to improve patient outcomes in ALS. PATIENT CONCERNS: The patient, a 75-year-old East Asian male, manifested an insidious onset of right-hand weakness advancing with dysarthria. Comprehensive Next-generation sequencing analysis identified variants in specific genes consistent with ALS diagnosis. DIAGNOSES: ALS diagnosis is based on El Escorial diagnostic criteria. INTERVENTIONS: This study introduces a novel therapeutic approach using artificial intelligence phenotypic response surface (AI-PRS) technology to customize personalized drug-dose combinations for ALS. The patient underwent a series of phases of AI-PRS-assisted trials, initially incorporating a 4-drug combination of Ibudilast, Riluzole, Tamoxifen, and Ropinirole. Biomarkers and regular clinical assessments, including nerve conduction velocity, F-wave, H-reflex, electromyography, and motor unit action potential, were monitored to comprehensively evaluate treatment efficacy. OUTCOMES: Neurophysiological assessments supported the ALS diagnosis and revealed the co-presence of diabetic polyneuropathy. Hypotension during the trial necessitated an adaptation to a 2-drug combinational trial (ibudilast and riluzole). Disease progression assessment shifted exclusively to clinical tests of muscle strength, aligning with the patient's well-being. LESSONS: The study raises the significance of personalized therapeutic strategies in ALS by AI-PRS. It also emphasizes the adaptability of interventions based on patient-specific responses. The encountered hypotension incident highlights the importance of attentive monitoring and personalized adjustments in treatment plans. The described therapy using AI-PRS, offering personalized drug-dose combinations technology is a potential approach in treating ALS. The promising outcomes warrant further evaluation in clinical trials for searching a personalized, more effective combinational treatment for ALS patients.

Epidemiology and analysis of SARS-CoV-2 Omicron subvariants BA.1 and 2 in Taiwan.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first detected in October 2021, possessed many mutations compared to previous variants. We aimed to identify and analyze SARS-CoV-2 Omicron subvariants among coronavirus disease 2019 (COVID-19) patients between January 2022 and September 2022 in Taiwan. The results revealed that BA.2.3.7, featuring K97E and G1251V in the spike protein compared with BA.2, emerged in March 2022 and persistently dominated between April 2022 and August 2022, resulting in the largest COVID-19 outbreak since 2020. The accumulation of amino acid (AA) variations, mainly AA substitution, in the spike protein was accompanied by increasing severity in Omicron-related COVID-19 between April 2022 and January 2023. Older patients were more likely to have severe COVID-19, and comorbidity was a risk factor for COVID-19-related mortality. The accumulated case fatality rate (CFR) dropped drastically after Omicron variants, mainly BA.2.3.7, entered Taiwan after April 2022, and the CFR was 0.16% in Taiwan, which was lower than that worldwide (0.31%) between April 2021 and January 2023. The relatively low CFR in Omicron-related COVID-19 patients can be attributed to adjustments to public health policies, promotion of vaccination programs, effective antiviral drugs, and the lower severity of the Omicron variant.

Metformin Adherence Reduces the Risk of Dementia in Patients With Diabetes: A Population-based Cohort Study.

OBJECTIVE: Metformin is widely used as the first-line drug for type 2 diabetes mellitus and has numerous benefits apart from lowering blood glucose. However, metformin-retained regimen is challenged by newly launching, powerful glucose-lowering antiglycemic agents. This population-based cohort study examined the association between metformin adherence and the risk of dementia and Parkinson's disease (PD). METHODS: Diabetic patients with metformin-included combination antiglycemic therapy were identified from the National Health Insurance Research Database and categorized into metformin-adherent and -nonadherent groups according to the medical record of the first year prescription. Patients contraindicated with metformin, severe diabetic complications, and poor drug compliance were excluded. The study outcome was the diagnosis of dementia or PD. RESULTS: A total of 31 384 matched pairs were included after using propensity score matching and both groups were followed up for an average of 5 years. Metformin adherence was associated with a significantly lower risk of dementia (adjusted hazard risk ratio = 0.72, P < .001) but not PD (adjusted hazard risk ratio = 0.97, P = .825). Subgroup analysis revealed that the risk of dementia was significantly reduced in metformin-adherent patients, both male and female, aged >65 or ≤ 65 years, and with or without concurrent insulin treatment. This effect was not influenced by concurrent insulin treatment, which may eliminate the bias caused by the severity of diabetes mellitus. CONCLUSION: Despite the launching of numerous new oral antiglycemic agents, metformin may provide further benefit on lowering risk of dementia beyond conventional glycemic control according to the real-world evidence.

Logistic regression and artificial neural network-based simple predicting models for obstructive sleep apnea by age, sex, and body mass index.

Age, sex, and body mass index (BMI) were associated with obstructive sleep apnea (OSA). Although various methods have been used in OSA prediction, this study aimed to develop predictions using simple and general predictors incorporating machine learning algorithms. This single-center, retrospective observational study assessed the diagnostic relevance of age, sex, and BMI for OSA in a cohort of 9, 422 patients who had undergone polysomnography (PSG) between 2015 and 2020. The participants were randomly divided into training, testing, and independent validation groups. Multivariable logistic regression (LR) and artificial neural network (ANN) algorithms used age, sex, and BMI as predictors to develop risk-predicting models for moderate-and-severe OSA. The training-testing dataset was used to assess the model generalizability through five-fold cross-validation. We calculated the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the independent validation set to assess the performance of the model. The results showed that age, sex, and BMI were significantly associated with OSA. The validation AUCs of the generated LR and ANN models were 0.806 and 0.807, respectively. The independent validation set's accuracy, sensitivity, specificity, PPV, and NPV were 76.3%, 87.5%, 57.0%, 77.7%, and 72.7% for the LR model, and 76.4%, 87.7%, 56.9%, 77.7%, and 73.0% respectively, for the ANN model. The LR- and ANN-boosted models with the three simple parameters effectively predicted OSA in patients referred for PSG examination and improved insight into risk stratification for OSA diagnosis.

Transmembrane stem cell factor protein therapeutics enhance revascularization in ischemia without mast cell activation.

Stem cell factor (SCF) is a cytokine that regulates hematopoiesis and other biological processes. While clinical treatments using SCF would be highly beneficial, these have been limited by toxicity related to mast cell activation. Transmembrane SCF (tmSCF) has differential activity from soluble SCF and has not been explored as a therapeutic agent. We created novel therapeutics using tmSCF embedded in proteoliposomes or lipid nanodiscs. Mouse models of anaphylaxis and ischemia revealed the tmSCF-based therapies did not activate mast cells and improved the revascularization in the ischemic hind limb. Proteoliposomal tmSCF preferentially acted on endothelial cells to induce angiogenesis while tmSCF nanodiscs had greater activity in inducing stem cell mobilization and recruitment to the site of injury. The type of lipid nanocarrier used altered the relative cellular uptake pathways and signaling in a cell type dependent manner. Overall, we found that tmSCF-based therapies can provide therapeutic benefits without off target effects.

Role of Fracture Risk Assessment Tool and Bone Turnover Markers in Predicting All-Cause and Cardiovascular Mortality in Hemodialysis Patients.

Background: Fracture Risk Assessment Tool (FRAX) and bone turnover markers (BTMs) predict fractures in the general population. However, the role of FRAX and BTMs in predicting mortality remains uncertain in hemodialysis (HD) patients. Methods: One hundred and sixty-four HD patients stratified by low or high risk of 10-year fracture probability using FRAX. High risk of fracture was defined as 10-year probability of hip fracture ≥3% or major osteoporotic fracture ≥20%. The association of high risk of fracture and BTMs with all-cause mortality and cardiovascular (CV) mortality were evaluated using multivariate-adjusted Cox regression analysis. Results: Eighty-five (51.8%) patients were classified as high risk of fracture based on FRAX among 164 HD patients. During a mean follow-up period of 3.5 ± 1.0 years, there were 39 all-cause deaths and 23 CV deaths. In multivariate-adjusted Cox regression, high risk of fracture based on FRAX was independently associated with all-cause mortality [hazard ratio (HR): 2.493, 95% confidence interval (CI): 1.026-6.056, p = 0.044) but not with CV mortality (HR: 2.129, 95% CI: 0.677-6.700, p = 0.196). There were no associations between BTMs and mortality risk. Furthermore, lower geriatric nutritional risk index (GNRI) was significantly associated with increased CV mortality (HR: 0.888, 95% CI: 0.802-0.983, p = 0.022) after adjusting by confounding variables. Conclusion: High risk of fracture using FRAX was an independent predictor of all-cause mortality in patients undergoing HD. FRAX, rather than BTMs, has an important role of prognostic significance in HD patients.

Defect Inspection Techniques in SiC.

With the increasing demand of silicon carbide (SiC) power devices that outperform the silicon-based devices, high cost and low yield of SiC manufacturing process are the most urgent issues yet to be solved. It has been shown that the performance of SiC devices is largely influenced by the presence of so-called killer defects, formed during the process of crystal growth. In parallel to the improvement of the growth techniques for reducing defect density, a post-growth inspection technique capable of identifying and locating defects has become a crucial necessity of the manufacturing process. In this review article, we provide an outlook on SiC defect inspection technologies and the impact of defects on SiC devices. This review also discusses the potential solutions to improve the existing inspection technologies and approaches to reduce the defect density, which are beneficial to mass production of high-quality SiC devices.

Benefits of Caregiver Counseling in Patients with Dementia: A Retrospective Observational Study.

INTRODUCTION: Patients with dementia have a 1.42 times higher risk of hospitalization than those without. Preparing and educating caregivers by counseling may attenuate the frequency of hospitalization and the financial burden on the health-care system. We conducted a retrospective observational study to verify whether caregiver counseling would benefit patients with mild cognitive impairment (MCI) or dementia. METHODS: The primary caregivers of patients with MCI or dementia at our Dementia Center from January 2017 to December 2018 were included in this study. Of the 532 caregivers who received counseling on caregiving for patients with dementia, 350 with complete data were included. The incidences of the patients' emergency department visits, hospitalizations, and durations of hospitalizations in 2 years prior to and after their caregivers received counseling were compared. A paired t test was used to test the frequency of patients' hospitalizations and emergency visits before and after counseling, and a p value of less than 0.05 was considered significant. RESULTS: The incidence of emergency visits (before counseling: 0.67 times/year, standard deviation [SD] = 0.823; after counseling: 0.25 times/year, SD = 0.549; p < 0.001) and hospitalizations (before counseling: 1.104 times/year, SD = 0.882; after counseling: 0.719 times/year, SD = 0.642; p < 0.001) decreased significantly after caregivers received counseling. The durations of hospitalization before and after counseling were 9.74 (SD = 6.940) days and 9.23 (SD = 6.908) days, respectively (p = 0.136). CONCLUSION: Counseling for caregivers of patients with MCI or dementia can significantly decrease the incidences of patients' emergency visits and hospitalizations but not durations of hospitalization. In multifaceted disease like dementia, counseling for caregivers is beneficial and reduces the burden on the health-care system. Further large-scale studies are warranted to verify this finding.

Retinal Diseases and Parkinson Disease: A Population-Based Study.

INTRODUCTION: Patients with Parkinson disease (PD) tend to have ophthalmic symptoms. Retinal diseases are associated with central nervous system diseases, especially neurodegenerative diseases. Here, we investigated the association of retinal diseases with PD, especially the temporal relationship before and after PD diagnosis. METHODS: Data were obtained from the National Health Insurance Research Database of Taiwan. In total, 21,845 patients with newly diagnosed PD were matched with four controls each on the basis of propensity score. This study was bidirectional. A case-control study evaluated the adjusted odds ratio (aOR) of retinal disease before PD diagnosis by using conditional logistic regression. Furthermore, a cohort study evaluated the adjusted subdistribution hazard ratio (aSHR) for new-onset retinal and optic nerve diseases after PD diagnosis by using competing risk analysis. The association between PD with optic nerve diseases and glaucoma (another common ophthalmic diseases with the consequence of retinal dysfunction) were also analyzed as reference. RESULTS: In the case-control study, PD was found to be significantly comorbid with recent and remote retinal disease [recent: ≤ 5 years, aOR: 1.12, 95% confidence interval (CI): 1.03-1.23; remote: > 5 years, aOR: 1.18, 95% CI: 1.04-1.34]. No similar association was identified between optic nerve disease or glaucoma with PD. In the cohort study, patients with PD were found to have a low risk of retinal disease in short-term (≤ 5 years, aSHR: 0.81, 95% CI: 0.71-0.93) and long-term (> 5 years, aSHR: 0.82, 95% CI: 0.72-0.93) follow-up. CONCLUSION: The study findings demonstrated that patients with prediagnostic PD were at greater risk of retinal disease than non-PD participants, but the risk reversed afterward. Thus, retinal disease may be a premotor manifestation of PD, and there may be some possible effect of dopamine supplements on retina.

Sex Difference in the Associations among Obesity-Related Indices with Metabolic Syndrome in Patients with Type 2 Diabetes Mellitus.

Background: The aim of this study was to investigate the associations among obesity-related indices and MetS in diabetic patients, and explore sex differences in these associations. Methods: Patients with type 2 DM were included from two hospitals in southern Taiwan. The Adult Treatment Panel III criteria for an Asian population were used to define MetS. In addition, the following obesity-related indices were evaluated: waist-to-height ratio, waist-hip ratio (WHR), conicity index (CI), body mass index (BMI), body roundness index, body adiposity index, lipid accumulation product (LAP), abdominal volume index, visceral adiposity index (VAI), abdominal volume index and triglyceride-glucose index. Results: A total of 1,872 patients with type 2 DM (mean age 64.0 ± 11.3 years, 808 males and 1,064 females) were enrolled. The prevalence rates of MetS were 59.8% and 76.4% in the males and female (p < 0.001), respectively. All of the obesity-related indices were associated with MetS in both sex (all p < 0.001). LAP and BMI had the greatest areas under the receiver operating characteristic curves in both sex. In addition, the interactions between BMI and sex (p = 0.036), WHR and sex (p = 0.016), and CI and sex (p = 0.026) on MetS were statistically significant. Conclusions: In conclusion, this study demonstrated significant relationships between obesity-related indices and MetS among patients with type 2 DM. LAP and VAI were powerful predictors in both sex. The associations of BMI, WHR and CI on MetS were more significant in the men than in the women.

GBP5 Repression Suppresses the Metastatic Potential and PD-L1 Expression in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype because of its high metastatic potential. Immune evasion due to aberrant expression of programmed cell death ligand 1 (PD-L1) has also been reported recently in metastatic TNBC. However, the mechanism underlying metastatic progression and PD-L1 upregulation in TNBC is still largely unknown. Here, we found that guanylate binding protein 5 (GBP5) is expressed in higher levels in TNBC tissues than in non-TNBC and normal mammary tissues and serves as a poorer prognostic marker in breast cancer patients. Transwell cultivation indicated that GBP5 expression is causally related to cellular migration ability in the detected TNBC cell lines. Moreover, the computational simulation of the gene set enrichment analysis (GSEA) program against the GBP5 signature generated from its coexpression with other somatic genes in TNBC revealed that GBP5 upregulation may be associated with the activation of interferon gamma (IFN-γ)-responsive and NF-κB-related signaling cascades. In addition, we found that the coexpression of GBP5 with PD-L1 was significantly positive correlation in TNBC tissues. Robustly, our data showed that GBP5 knockdown in TNBC cells harboring a higher GBP5 level dramatically suppresses the number of migrated cells, the activity of IFN-γ/STAT1 and TNF-α/NF-κB signaling axes, and the expression of PD-L1. Importantly, the signature combining a higher GBP5 and PD-L1 level predicted the shortest time interval of brain metastasis in breast cancer patients. These findings not only uncover the oncogenic function of GBP5 but also provide a new strategy to combat metastatic/immunosuppressive TNBC by targeting GBP5 activity.

GBP5 Serves as a Potential Marker to Predict a Favorable Response in Triple-Negative Breast Cancer Patients Receiving a Taxane-Based Chemotherapy.

Pre-operative (neoadjuvant) or post-operative (adjuvant) taxane-based chemotherapy is still commonly used to treat patients with triple-negative breast cancer (TNBC). However, there are still no effective biomarkers used to predict the responsiveness and efficacy of taxane-based chemotherapy in TNBC patients. Here we find that guanylate-binding protein 5 (GBP5), compared to other GBPs, exhibits the strongest prognostic significance in predicting TNBC recurrence and progression. Whereas GBP5 upregulation showed no prognostic significance in non-TNBC patients, a higher GBP5 level predicted a favorable recurrence and progression-free condition in the TNBC cohort. Moreover, we found that GBP5 expression negatively correlated with the 50% inhibitory concentration (IC50) of paclitaxel in a panel of TNBC cell lines. The gene knockdown of GBP5 increased the IC50 of paclitaxel in the tested TNBC cells. In TNBC patients receiving neoadjuvant or adjuvant chemotherapy, a higher GBP5 level strongly predicted a good responsiveness. Computational simulation by the Gene Set Enrichment Analysis program and cell-based assays demonstrated that GBP5 probably enhances the cytotoxic effectiveness of paclitaxel via activating the Akt/mTOR signaling axis and suppressing autophagy formation in TNBC cells. These findings suggest that GBP5 could be a good biomarker to predict a favorable outcome in TNBC patients who decide to receive a taxane-based neoadjuvant or adjuvant therapy.

Exosomal TAR DNA-binding protein-43 and neurofilaments in plasma of amyotrophic lateral sclerosis patients: A longitudinal follow-up study.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease with characteristic of progressive general muscle weakness and atrophy. ALS is still lack of efficient treatment and laboratory biomarkers. In this study, we longitudinally examined ALS patients' peripheral blood to search potential biomarkers. 18 ALS patients aged between 20 and 65 years were recruited in a clinical trial and longitudinal plasma samples were obtained and analyzed at baseline, 1, 3, 6 and 12 months follow up. Neurofilament light chain (NFL), phosphorylated neurofilament heavy chain (pNFH) by ELISA and exosomal TAR DNA-binding protein-43 (TDP-43) ratio were measured by flow cytometry assay in isolated exosomes RESULTS: Exosomal TDP-43 ratio significantly changed in 3-month (increased 60.8 ± 18.9%, p = 0.0005) and 6-month (increased 60.2 ± 32.6%, p = 0.0291) follow-up and close to significance at 12-month follow-up (increased 12.8 ± 10.8%, p = 0.0524). When subclassifying patients into rapid and slow progression groups, NFL but not pNFH is significantly higher in the rapid progression group at baseline (22.74 ± 1.66 pg/mL vs. 43.96 ± 12.87 pg/mL, p = 0.0136) and at 3-month follow-up (28.40 ± 3.39 pg/mL vs. 40.33 ± 5.44 pg/mL, p = 0.0356). CONCLUSION: In this study, we found exosomal TDP-43 ratio was increasing along with follow-up at 3 and 6 months and NFL levels in plasma was associated with rapid progression in ALS patients. In addition to NFL, exosomal TDP-43 ratio might be a potential candidate of biomarkers for ALS long-term follow-up studies.

Tamoxifen for amyotrophic lateral sclerosis: A randomized double-blind clinical trial.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is the most common cause of motor neuron disease, and effective treatment for ALS is still lacking. Transactive response (TAR) -DNA-binding protein-43 (TDP-43) is aggregated in the neurons of ALS patients. Animal studies shown TDP-43 aggregation can be attenuated by enhancing autophagy by tamoxifen. However, its beneficial effects for ALS patients remain unknown. METHODS: Eighteen patients with ALS without mutations in superoxide dismutase-1 (SOD-1) or fused in sarcoma (FUS) genes were randomly assigned into the tamoxifen 40 mg/day or placebo group in a double-blinded manner and all were given riluzole twice daily. Participants were followed up at 1, 3, 6, and 12 months. The primary end point was time to death or dependence on mechanical ventilation. Secondary end points were decline of the revised ALS Functional Rating Scale (ALSFRS-R) score and pulmonary function measured by forced vital capacity (FVC). RESULTS: Ten participants were randomly assigned in the treatment group with tamoxifen, 7 finished trial, 1 reach primary endpoint; while 8 participants in the placebo group, 2 finished trial and 2 reach primary end point. The proportion of participants reaching the primary end point was lower in the tamoxifen group but did not reach statistical significance. At the 1-, 3-, and 6-month follow-up, the average decline rates of the ALSFRS-R score were slower in the tamoxifen group. No significant difference was observed in FVC and ALSFRS-R score at 12 months between groups. CONCLUSION: Tamoxifen exerted only a modest effect on attenuate progression for 6 months in this small trial. Additional larger scale studies should be necessary to confirm whether enhancing autophagy can attenuate ALS progression.

Genome wide analysis of gene expression changes in skin from patients with type 2 diabetes.

Non-healing chronic ulcers are a serious complication of diabetes and are a major healthcare problem. While a host of treatments have been explored to heal or prevent these ulcers from forming, these treatments have not been found to be consistently effective in clinical trials. An understanding of the changes in gene expression in the skin of diabetic patients may provide insight into the processes and mechanisms that precede the formation of non-healing ulcers. In this study, we investigated genome wide changes in gene expression in skin between patients with type 2 diabetes and non-diabetic patients using next generation sequencing. We compared the gene expression in skin samples taken from 27 patients (13 with type 2 diabetes and 14 non-diabetic). This information may be useful in identifying the causal factors and potential therapeutic targets for the prevention and treatment of diabetic related diseases.

Validation of the Test of Visual Perceptual Skills-Third Edition in patients with stroke.

PURPOSE: The Test of Visual Perceptual Skills-Third Edition (TVPS-3) with seven subscales has been used to assess visual perception in patients with stroke. The purpose of this study was to investigate ecological validity, convergent validity, and discriminative validity of the TVPS-3 in patients with stroke. METHODS: One hundred patients were assessed with the TVPS-3, two measures of activities of daily living, and two cognitive measures. To examine ecological validity, we calculated correlations (Pearson's r) among the TVPS-3 and two measures of activities of daily living. To examine convergent validity, correlations (r) were estimated among the TVPS-3 and two cognitive measures. To examine discriminative validity, independent t-test was used to compare the two groups with different levels of disability and to detect whether there were statistically significant differences in the TVPS-3 between these groups. RESULTS: The correlations were 0.21-0.48 among the TVPS-3 and two measures of activities of daily living. The correlations were 0.29-0.68 among the TVPS-3 and two cognitive measures. Between the two groups, the t-test results showed statistically significant difference (p < 0.05) for the overall scale and the five subscales of the TVPS-3. CONCLUSIONS: The TVPS-3 has acceptable convergent validity, ecological validity, and discriminative validity and is useful to assess the visual perception in patients with stroke. Implications for rehabilitation The Test of Visual Perceptual Skills-Third Edition is a motor free visual perception test, which is an adequate tool for use in patients with stroke. The Test of Visual Perceptual Skills-Third Edition showed acceptable ecological validity, convergent validity, and discriminative validity in patients with stroke.

Evaluation of the effects of glucose on osmolal gap using freezing point depression and vapor pressure methods.

The measurement of serum osmolality, and the calculation of osmolal gap (OG) from a calculated osmolality are widely used in clinical and emergency medicine. In this study, the possible effects of blood glucose on OG were investigated by freezing point depression and vapor pressure methods. The concentrations of sodium, glucose, blood urea nitrogen and osmolalities of 2640 samples were measured. There were two methods for calculating serum osmolality: freezing point depression method (n = 2399) and vapor pressure method (n = 241). The OG was positively associated with glucose in glucose 110-450 mg/dL (r = 0.191, p < 0.001) and glucose > 450 mg/dL (r = 0.372, p < 0.001), but not in glucose < 110 mg/dL (r = 0.017, p = 0.711) in freezing point depression method. However, OG had no correlation with glucose regardless of glucose level in vapor pressure method. In freezing point depression method, compared with the groups of glucose <110 and 110-450 mg/dL, the group with glucose >450 mg/dL had higher OG (p < 0.001) and higher prevalence of OG > 10 mOsm/Kg H2O (p < 0.001). Our study demonstrated that OG is impacted by increasing blood glucose concentration using freezing point depression method, special attention should be made to blood glucose concentrations when using freezing point depression method to determine OG.

Hyperuricemia is associated with decreased changes in heart rate variability after hemodialysis in non-diabetic patients.

Hyperuricemia has been associated with low heart rate variability (HRV), however whether there is an association between uric acid (UA) and HRV changes after hemodialysis (HD) is unknown. The aim of this study was to investigate the role of UA in HRV changes before and after HD in non-diabetic patients. Ninety-six non-diabetic patients under maintenance HD were enrolled. HRV was examined to assess changes before and after HD. A change in HRV (ΔHRV) was calculated as post-HD HRV minus pre-HD HRV. Compared to the patients with a UA level ≦ 7 mg/dL, those with a UA level > 7 mg/dL had lower ∆high frequency (HF)% (p = 0.027). UA was negatively associated with ∆HF% (r = -0.247, p = 0.015) and ∆low frequency (LF)/HF (r = -0.236, p = 0.021) in the non-diabetic patients undergoing HD. Furthermore, in multivariate analysis after adjustments for demographic, clinical, and biochemical characteristics and medications, UA was independently associated with ∆HF% (per 1 mg/dL, unstandardized coefficient ß = -2.892; 95% CI, -5.066 to -0.717; p = 0.010) and ∆LF/HF (per 1 mg/dL, unstandardized coefficient ß = -0.165; 95% CI, -0.291 to -0.038; p = 0.011). Hyperuricemia contributed to lesser HF% and LF/HF increase after HD in the non-diabetic patients, reflecting a state of impaired sympatho-vagal equilibrium in non-diabetic HD patients with hyperuricemia. Lowering UA levels may have the potential to improve increased HRV in non-diabetic HD patients.

Association of type 2 diabetes mellitus and ratio of transmitral E wave velocity to early diastole mitral velocity with cardiovascular events in chronic kidney disease.

The association between DM and left ventricular diastolic dysfunction, assessed using the ratio of peak early transmitral filling wave velocity (E) to early diastolic velocity of mitral annulus (Ea), with cardiovascular (CV) outcomes in patients with chronic kidney disease (CKD) remains uncertain. This study included 356 CKD stage 3-5 patients underwent echocardiography. All patients were classified into four groups based on the presence of DM and E/Ea ≤ or > 9. CV events included CV death, hospitalization for heart failure, unstable angina or nonfatal myocardial infarction, sustained ventricular arrhythmia, transient ischemic attack, and stroke. There were 58 CV events during the mean observation period of 25.0 months. A combination of the presence of DM and E/Ea > 9 (vs. a combination of non-DM and E/Ea ≤ 9) was associated with CV events in unadjusted model (hazard ratio [HR], 6.990; 95% confidence interval [CI], 2.753-17.744; p < 0.001), and in a multivariate adjusted model (HR, 3.037; 95% CI, 2.088-7.177; p = 0.025). In the patients without DM, the E/Ea ratio (p = 0.033) improved the prediction of CV events, compared to the E/Ea ratio (p = 0.018), left atrial diameter (p = 0.016) and left ventricular mass index (p = 0.001) in the patients with DM. The combination of DM and left ventricular diastolic dysfunction was associated with CV events in patients with CKD stage 3-5. Assessments of DM status and E/Ea ratio may facilitate identifying high-risk patient population of unfavorable CV outcomes.

Neuroprotective Functions Through Inhibition of ER Stress by Taurine or Taurine Combination Treatments in a Rat Stroke Model.

Taurine, as a free amino acid, is found at high levels in many tissues including brain, heart and skeletal muscle and is known to demonstrate neuroprotective effects in a range of disease conditions including stroke and neurodegenerative disease. Using in vitro culture systems we have demonstrated that taurine can elicit protection against endoplasmic reticulum stress (ER stress) from glutamate excitotoxicity or from excessive reactive oxygen species in PC12 cells or rat neuronal cultures. In our current investigation we hypothesized that taurine treatment after stroke in the rat middle cerebral artery occlusion (MCAO) model would render protection against ER stress processes as reflected in decreased levels of expression of ER stress pathway components. We demonstrated that taurine elicited high level protection and inhibited both ATF-6 and IRE-1 ER stress pathway components. As ischemic stroke has a complex pathology it is likely that certain combination treatment approaches targeting multiple disease mechanisms may have excellent potential for efficacy. We have previously employed the partial NMDA antagonist DETC-MeSO to render protection against in vivo ischemic stroke using a rat cerebral ischemia model. Here we tested administration of subcutaneous administration of 0.56 mg/kg DETC-MeSO or 40 mg/kg of taurine separately or as combined treatment after a 120 min cerebral ischemia in the rat MCAO model. Neither drug alone demonstrated protection at the low doses employed. Remarkably however the combination of low dose DETC-MeSO plus low dose taurine conferred a diminished infarct size and an enhanced Neuroscore (reflecting decreased neurological deficit). Analysis of ER stress markers pPERK, peIF-2-alpha and cleaved ATF-6 all showed decreased expression demonstrating that all 3 ER stress pathways were inhibited concurrent with a synergistic protective effect by the post-stroke administration of this DETC-MeSO-taurine combination treatment.