Peripheral Nerve Denervation in Streptozotocin-Induced Diabetic Rats Is Reduced by Cilostazol.

Background and Objective: Our previous study demonstrated that consistent treatment of oral cilostazol was effective in reducing levels of painful peripheral neuropathy in streptozotocin-induced type I diabetic rats. As diabetic neuropathy is characterized by hyperglycemia-induced nerve damage in the periphery, this study aims to examine the neuropathology as well as the effects of cilostazol treatments on the integrity of peripheral small nerve fibers in type I diabetic rats. Materials and Methods: A total of ninety adult male Sprague-Dawley rats were divided into the following groups: (1) naïve (control) group; (2) diabetic rats (DM) group for 8 weeks; DM rats receiving either (3) 10 mg/kg oral cilostazol (Cilo10), (4) 30 mg/kg oral cilostazol (Cilo30), or (5) 100 mg/kg oral cilostazol (Cilo100) for 6 weeks. Pain tolerance thresholds of hind paws toward thermal and mechanical stimuli were assessed. Expressions of PGP9.5, P2X3, CGRP, and TRPV-1 targeting afferent nerve fibers in hind paw skin and glial cells in the spinal dorsal horn were examined via immunohistochemistry and immunofluorescence. Results: Oral cilostazol ameliorated the symptoms of mechanical allodynia but not thermal analgesia in DM rats. Significant reductions in PGP9.5-, P2X3-, CGRP, and TRPV-1-labeled penetrating nerve fibers in the epidermal layer indicated denervation of sensory nerves in the hind paw epidermis of DM rats. Denervation significantly improved in groups that received Cilo30 and Cilo100 in a dose-dependent manner. Cilostazol administration also suppressed microglial hyperactivation and increased astrocyte expressions in spinal dorsal horns. Conclusions: Oral cilostazol ameliorated hyperglycemia-induced peripheral small nerve fiber damage in the periphery of diabetic rats and effectively mitigated diabetic neuropathic pain via a central sensitization mechanism. Our findings present cilostazol not only as an effective option for managing symptoms of neuropathy but also for deterring the development of diabetic neuropathy in the early phase of type I diabetes.

AAV-glycine receptor α3 alleviates CFA-induced inflammatory pain by downregulating ERK phosphorylation and proinflammatory cytokine expression in SD rats.

BACKGROUND: Glycine receptors (GlyRs) play key roles in the processing of inflammatory pain. The use of adeno-associated virus (AAV) vectors for gene therapy in human clinical trials has shown promise, as AAV generally causes a very mild immune response and long-term gene transfer, and there have been no reports of disease. Therefore, we used AAV for GlyRα1/3 gene transfer in F11 neuron cells and into Sprague-Dawley (SD) rats to investigate the effects and roles of AAV-GlyRα1/3 on cell cytotoxicity and inflammatory response. METHODS: In vitro experiments were performed using plasmid adeno-associated virus (pAAV)-GlyRα1/3-transfected F11 neurons to investigate the effects of pAAV-GlyRα1/3 on cell cytotoxicity and the prostaglandin E2 (PGE2)-mediated inflammatory response. In vivo experiment, the association between GlyRα3 and inflammatory pain was analyzed in normal rats after AAV-GlyRα3 intrathecal injection and after complete Freund's adjuvant (CFA) intraplantar administration. Intrathecal AAV-GlyRα3 delivery into SD rats was evaluated in terms of its potential for alleviating CFA-induced inflammatory pain. RESULTS: The activation of mitogen-activated protein kinase (MAPK) inflammatory signaling and neuronal injury marker activating transcription factor 3 (ATF-3) were evaluated by western blotting and immunofluorescence; the level of cytokine expression was measured by ELISA. The results showed that pAAV/pAAV-GlyRα1/3 transfection into F11 cells did not significantly reduce cell viability or induce extracellular signal-regulated kinase (ERK) phosphorylation or ATF-3 activation. PGE2-induced ERK phosphorylation in F11 cells was repressed by the expression of pAAV-GlyRα3 and administration of an EP2 inhibitor, GlyRαs antagonist (strychnine), and a protein kinase C inhibitor. Additionally, intrathecal AAV-GlyRα3 administration to SD rats significantly decreased CFA-induced inflammatory pain and suppressed CFA-induced ERK phosphorylation, did not induce obvious histopathological injury but increased ATF-3 activation in dorsal root ganglion (DRGs). CONCLUSIONS: Antagonists of the prostaglandin EP2 receptor, PKC, and glycine receptor can inhibit PGE2-induced ERK phosphorylation. Intrathecal AAV-GlyRα3 administration to SD rats significantly decreased CFA-induced inflammatory pain and suppressed CFA-induced ERK phosphorylation, did not significantly induce gross histopathological injury but elicited ATF-3 activation. We suggest that PGE2-induced ERK phosphorylation can be modulated by GlyRα3, and AAV-GlyRα3 significantly downregulated CFA-induced cytokine activation.

Sciatic Nerve Intrafascicular Injection Induces Neuropathy by Activating the Matrix Modulators MMP-9 and TIMP-1.

Background: Peripheral nerve block (PNB) under echo guidance may not prevent intrafascicular anesthetic injection-induced nerve injury. This study investigated whether unintended needle piercing alone, or the intrafascicular nerve injectant could induce neuropathy. Methods: 120 adult male Sprague-Dawley rats were divided into four groups: 1) group S, only the left sciatic nerve was exposed; 2) group InF-P, the left sciatic nerve was exposed and pierced with a 30 G needle; 3) group InF-S, left sciatic nerve was exposed and injected with saline (0.9% NaCl 30 µL); 4) group InF-R, left sciatic nerve was exposed and injected with 0.5% (5 mg/mL, 30 µL) ropivacaine. Behaviors of thermal and mechanical stimuli responses from hindpaws, sciatic nerve vascular permeability and tight junction protein expression, and macrophage infiltration were assessed. Pro-inflammatory cytokine expression and TIMP-1 and MMP-9 activation at the injection site and the swollen, and distal sites of the sciatic nerve were measured by cytokine array, western blotting, and immunofluorescence of POh14 and POD3. Results: Intrafascicular saline and ropivacaine into the sciatic nerve, but not needle piercing alone, significantly induced mechanical allodynia that lasted for seven days. In addition, the prior groups increased vascular permeability and macrophage infiltration, especially in the swollen site of the sciatic nerve. Thermal hypersensitivity was induced and lasted for only 3 days after intrafascicular saline injection. Obvious upregulation of TIMP-1 and MMP-9 on POh6 and POh14 occurred regardless of intrafascicular injection or needle piercing. Compared to the needle piercing group, the ratio of MMP-9/TIMP-1 was significantly higher in the intrafascicular injectant groups at the injected and swollen sites of the sciatic nerve. Although no gross changes in the expressions of tight junction proteins (TJPs) claudin-5 and ZO-1, the TJPs turned to apparent fragmentation and fenestration-like degenerative change in swollen endothelial cells and thickened microvessels. Conclusion: Intrafascicular nerve injection is a distinct mechanism that induces neuropathy. It is likely that the InF nerve injection-induced neuropathy was largely due to dramatic, but transient, increases in enzymatic activities of MMP-9 and activating TIMP-1 in the operated nerves. The changes in enzymatic activities then contributed to certain levels of extracellular matrix degradation, which leads to increases in endoneurial vascular permeability.

Effects of Hyperbaric Oxygen Therapy on Serum Adhesion Molecules, and Serum Oxidative Stress in Patients with Acute Traumatic Brain Injury.

BACKGROUND: Serum concentrations of adhesion molecules and oxidative stress is thought to participate in the pathobiology of secondary brain injury after acute traumatic brain injury (TBI). We aimed to study the hypothesis that hyperbaric oxygen therapy (HBOT) both improves the adhesion molecules levels and antioxidant capacity. METHODS: Thirty blood samples from ten patients after acute TBI were obtained after injury and before and after HBOT. Four patients received early HBOT started two weeks after injury, four patients received late HBOT started ten weeks after injury and two patients did not receive HBOT and served as control in this study. The HBOT patients received total 30 times HBOT in six weeks period. RESULTS: Those serum biomarkers in patients with TBI had not significantly difference in glutathione (GSH), thiobarbituric acid reactive substances (TBARS), soluble intercellular cell adhesion-molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) concentrations on admission between early HBOT, late HBOT, and control group (p = 0.916, p = 0.98, p = 0.306, and p = 0.548, respectively). Serum GSH levels were higher at 10 weeks after injury in the early HBOT group than in the late HBOT group and control group (mean, 1.40 µmol/L, 1.16 µmol/L, and 1.05 µmol/L, respectively). Then the serum GSH level was increased at 18 weeks after injury in the late HBOT group (mean, 1.49 µmol/L). However, there was only statistically significant difference at Weeks 18 (p = 0.916, p = 0.463, and p = 0.006, at Week 2, Week 10, and Week 18, respectively). Serum TBARS levels were decreased at 10 weeks after injury in the early HBOT group than in the late HBOT group and control group (mean, 11.21 µmol/L, 17.23 µmol/L, and 17.14 µmol/L, respectively). Then the serum TBARS level was decreased at 18 weeks after injury in the late HBOT group (mean, 12.06 µmol/L). There was statistically significant difference after HBOT (p = 0.98, p = 0.007, and p = 0.018, at Week 2, Week 10, and Week 18, respectively). There was no statistically significant difference between the three groups on sICAM-1 and sVCAM-1 levels from Week 2 to Week 18. CONCLUSIONS: HBOT can improve serum oxidative stress in patients after TBI. These molecules may be added as evaluation markers in clinical practice. Perhaps in the future it may also become part of the treatment of patients after acute traumatic brain injury. Further large-scale study may be warrant.

Effects of Respiratory Muscle Training on Baroreflex Sensitivity, Respiratory Function, and Serum Oxidative Stress in Acute Cervical Spinal Cord Injury.

BACKGROUND: respiratory complications are a leading cause of morbidity and mortality in individuals with spinal cord injury (SCI). We examined the effects of respiratory muscle training (RMT) in patients with acute cervical SCI. METHODS: this prospective trial enrolled 44 adults with acute cervical SCI, of which twenty received RMT and twenty-four did not receive RMT. Respiratory function, cardiovascular autonomic function, and reactive oxidative species (ROS) were compared. The experimental group received 40-min high-intensity home-based RMT 7 days per week for 10 weeks. The control group received a sham intervention for a similar period. The primary outcomes were the effects of RMT on pulmonary and cardiovascular autonomic function, and ROS production in individuals with acute cervical SCI. RESULTS: significant differences between the two groups in cardiovascular autonomic function and the heart rate response to deep breathing (p = 0.017) were found at the 6-month follow-up. After RMT, the maximal inspiratory pressure (p = 0.042) and thiobarbituric acid-reactive substances (TBARS) (p = 0.006) improved significantly, while there was no significant difference in the maximal expiratory pressure. Significant differences between the two groups in tidal volume (p = 0.005) and the rapid shallow breathing index (p = 0.031) were found at 6 months. Notably, the SF-36 (both the physical (PCS) and mental (MCS) component summaries) in the RMT group had decreased significantly at the 6-month follow-up, whereas the clinical scores did not differ significantly (p = 0.333) after RMT therapy. CONCLUSIONS: High-intensity home-based RMT can improve pulmonary function and endurance and reduce breathing difficulties in patients with respiratory muscle weakness after injury. It is recommended for rehabilitation after spinal cord injury.

A fast and facile platform for fabricating phase-change materials-based drug carriers powered by chemical Marangoni effect.

Emulsions of oil droplets as drug carriers are typically formulated by emulsification, which is complex and time-consuming and requires high energy input. To address these concerns, a fast and facile method for fabricating lipid-based oil droplets, using propulsive forces that arise from the chemical Marangoni effect, is developed for the oral delivery of lipophilic drugs, such as vitamin D. The oil droplets are prepared by solubilizing vitamin D in a phase-changeable fatty acid with the addition of ethanol as an oil phase, which is then deposited on a water bath. As a result of the differing surface tensions of water and ethanol (chemical energy), propulsive Marangoni forces are generated (kinetic energy), rapidly spreading the oil phase into many tiny oil droplets. To prevent their coalescence, the generated oil droplets are solidified by reducing their environmental temperature. Following oral administration, the fluidity of the solidified droplets increases at body temperature; they can be further emulsified into the vitamin D-containing micelles by intestinal bile salts. The micelles are then taken up by the intestinal epithelial cells, enabling their contained vitamin D to be absorbed into systemic circulation, improving its oral bioavailability.

Angiotensin II receptor blockers valsartan and losartan improve survival rate clinically and suppress tumor growth via apoptosis related to PI3K/AKT signaling in nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a common type of head and neck cancer in Asia. Adverse effects occur in over 90% of NPC patients treated with radiotherapy or chemoradiation. Angiotensin II receptor blockers (ARBs) are commonly used to treat hypertension without serious adverse effects. However, the anticancer activity of ARBs in NPC remains unclear. METHODS: We investigated the survival impacts of ARBs among NPC patients in a retrospective study. The anticancer effects and related signaling pathways of the ARBs valsartan and losartan were also evaluated in vitro and in vivo. RESULT: A total of 927 patients with NPC who had hypertension were enrolled in the study, 272 (29.3%) of whom received ARBs. Kaplan-Meier analysis revealed that patients who used ARBs had higher rates of 5-year overall survival (OS; 87.8% vs 75.1%; P = .002) and disease-specific survival (DSS; 95.4% vs 77.7%; P < .001) than those who did not receive this treatment. Additionally, ARBs inhibited cell proliferation and induced apoptosis by increasing levels of cleaved caspase-3, cleaved caspase-9, and cytochrome C; the cell population in the sub-G1 phase; and caspase-3 activity in NPC-TW01 cells. ARBs inhibited tumor growth and angiogenesis via apoptosis in an NPC xenografts model. Interestingly, ARBs inhibited phosphorylation of PI3K/AKT signaling in vitro and in vivo, which is markedly attributed to their antitumor effects in NPC. CONCLUSION: These data indicate that ARBs not only improve 5-year OS and DSS among patients with NPC but also exert antiproliferative and antiangiogenesis effects by inducing apoptosis in NPC, supporting that ARBs may be promising agents for treatment of NPC.

Cilostazol Ameliorates Peripheral Neuropathic Pain in Streptozotocin-Induced Type I Diabetic Rats.

Background: Cilostazol is an antiplatelet agent with vasodilating, endothelial function restoration, and anti-inflammatory effects. This study aims to investigate the efficacy of oral cilostazol for preventing the development of diabetic peripheral neuropathy (DPN). Materials and Methods: Ninety adult male Sprague-Dawley rats were divided into five groups: 1) naïve (control); 2) diabetic (DM); 3) DM receiving 10 mg/kg cilostazol (cilo-10); 4) DM receiving 30 mg/kg cilostazol (cilo-30); and 5) DM receiving 100 mg/kg cilostazol (cilo-100). Hindpaw responses to thermal and mechanical stimuli were measured. Activation of microglia and astrocytes in the spinal dorsal horn (SDH) and expression of NaVs in the dorsal root ganglia (DRG) were examined with Western blots and immunofluorescence. Results: DM rats displayed decreased withdrawal thresholds to mechanical stimuli (mechanical allodynia) and blunted responses to thermal stimuli. In addition, the expression of microglia increased, but astrocytes were reduced in the SDH. Upregulation of Nav -1.1, 1.2, -1.3, -1.6, and -1.7 and downregulation of Nav-1.8 were observed in the DRG. The DM rats receiving cilostazol all returned DM-induced decrease in withdrawal threshold to mechanical stimuli and attenuated neuropathic pain. Additionally, all cilostazol treatments suppressed the level of activated microglial cells and ameliorated the DM-induced decline in astrocyte expression levels in the SDH. However, only the rats treated with cilo-100 demonstrated significant improvements to the aberrant NaV expression in the DRG. Conclusion: Oral cilostazol can blunt the responses of mechanical allodynia and has the potential to treat diabetic neuropathy by attenuating NaV and glial cell dysregulation.

Upregulation of miR-133a-3p in the Sciatic Nerve Contributes to Neuropathic Pain Development.

The micro (mi)RNAs expressed in the sciatic nerve of streptozotocin (STZ)-induced diabetic rats were evaluated in terms of their therapeutic potential in patients with diabetic neuropathic pain (DNP). Relative miRNA expression in sciatic nerve with DNP was analyzed using next-generation sequencing and quantitative PCR. Potential downstream targets of miRNAs were predicted using Ingenuity Pathway Analysis and the TargetScan database. In vitro experiments were performed using miR-133a-3p-transfected RSC96 Schwann cells. We performed micro-Western and Western blotting and immunofluorescence analyses to verify the role of miR-133a-3p. In vivo, the association between miR-133a-3p with DNP was analyzed via AAV-miR-133a-3p intraneural (intra-epineural but extrafascicular) injection into the sciatic nerve of normal rats or injection of an miR-133a-3p antagomir into the sciatic nerve of diabetes mellitus (DM) rats. miR-133a-3p mimics transfected into RSC96 Schwann cells increased VEGFR-2, p38α MAPK, TRAF-6, and PIAS3 expression and reduced NFκB p50 and MKP3 expression. In normal rats, AAV-miR-133a-3p delivery via intraneural injection into the sciatic nerve induced mechanical allodynia and p-p38 MAPK activation. In DM rats, miR-133a-3p antagomir administration alleviated DNP and downregulated p-p38 phosphorylation. Overexpression of miR-133a-3p in the sciatic nerve induced such pain. We suggest that miR-133a-3p is a potential therapeutic target for DNP.

Impact of oxidative stress on treatment outcomes in adult patients with sepsis: A prospective study.

PURPOSE: Oxidative stress has been shown to reflect on the development of sepsis and disease severity. In the present study, we evaluated the effects of increased levels of oxidative stress and decreased antioxidant coactivity in patients with sepsis, and the importance of oxidative stress on treatment outcomes. METHODS: Biomarkers of oxidative stress (thiobarbituric acid-reactive substances [TBARS]) and antioxidant capacity (glutathione peroxidase [GPx] and glutathione content [thiol]) were prospectively evaluated along with biochemical and clinical data in 100 patients with sepsis on days 1, 4, and 7 after admission. RESULTS: The TBARS level of the non-survivor group was significantly higher than that of the survivor group on day 1 and day 4 and negatively correlated with thiol upon admission. However, thiol was positively correlated with lactate concentration. The TBARS and lactate levels upon admission were independent predictors of fatality. CONCLUSIONS: We conclude that a TBARS cut-off value of 18.30 µM can be used to predict fatality, and an increase in the TBARS concentration by 1 µM will increase the fatality rate by 0.94%. In the panel of biomarkers, the TBARS assay can be considered as a prognostic biomarker for the treatment of patients with sepsis.

Factors Associated With Prolonged Mechanical Ventilation and Reventilation in Acute Cervical Spinal Cord Injury Patients.

MINI: In this study, respiratory function at the time of extubation can be useful optimal clinical guidelines for weaning and extubation attempts in patients with acute cervical spinal cord injury. Serum thiobarbituric acid-reactive substances level at admission can be a useful predictor for severity in acute cervical patients with spinal cord injury. STUDY DESIGN: Patients who had suffered from acute blunt cervical spinal cord injury (SCI) and admitted our hospital within 24 hours after injury were included in the study. OBJECTIVE: We compared the respiratory function and serum reactive oxidative stress (ROS) after acute cervical SCI, and tried to find out the valuable predictors of weaning in patients with acute cervical SCI. SUMMARY OF BACKGROUND DATA: Ventilation impairment is a major complication of acute cervical SCI. Evidence of oxygen radical formation in secondary injury from animal SCI models demonstrates an immediate postinjury increase in ROS production after SCI. We hypothesize that the serum ROS is associated with the severity of patients with acute cervical SCI. METHODS: Thirty-eight adult patients who had acute cervical SCI and 58 healthy volunteers were enrolled. Respiratory function at admission, at the time of extubation and at 48 hours after extubation, serum oxidative stress, Injury Severity Score and Japanese Orthopaedic Association score at admission were compared. RESULTS: The most notable predictor of mechanical ventilation more than 48 hours was serum thiobarbituric acid-reactive substances (TBARS) level at admission (P = 0.027), and the cut-off value of serum TBARS level was 731.7 µmol/L (sensitivity 87.5% and specificity 78.9%). For the reventilation ≤5 days, the notable predictors were respiratory function at the time of extubation (maximal inspiratory pressure, P = 0.040; maximal expiratory pressure, P = 0.020; and tidal volume, P = 0.036) and serum TBARS level at admission (P = 0.013), the cut-off value of serum TBARS level at admission was 762.3 µmol/L (sensitivity 100% and specificity 90.0%). CONCLUSION: In this study, respiratory function (maximal inspiratory pressure, maximal expiratory pressure, and tidal volume) at the time of extubation can be useful optimal clinical guidelines for weaning and extubation attempts in patients with acute cervical SCI. Serum TBARS level at admission can be a useful predictor for severity in acute cervical SCI patients. LEVEL OF EVIDENCE: 3.

Patients who had suffered from acute blunt cervical spinal cord injury (SCI) and admitted our hospital within 24 hours after injury were included in the study. We compared the respiratory function and serum reactive oxidative stress (ROS) after acute cervical SCI, and tried to find out the valuable predictors of weaning in patients with acute cervical SCI. Ventilation impairment is a major complication of acute cervical SCI. Evidence of oxygen radical formation in secondary injury from animal SCI models demonstrates an immediate postinjury increase in ROS production after SCI. We hypothesize that the serum ROS is associated with the severity of patients with acute cervical SCI. Thirty-eight adult patients who had acute cervical SCI and 58 healthy volunteers were enrolled. Respiratory function at admission, at the time of extubation and at 48 hours after extubation, serum oxidative stress, Injury Severity Score and Japanese Orthopaedic Association score at admission were compared. The most notable predictor of mechanical ventilation more than 48 hours was serum thiobarbituric acid-reactive substances (TBARS) level at admission (P = 0.027), and the cut-off value of serum TBARS level was 731.7 µmol/L (sensitivity 87.5% and specificity 78.9%). For the reventilation ≤5 days, the notable predictors were respiratory function at the time of extubation (maximal inspiratory pressure, P = 0.040; maximal expiratory pressure, P = 0.020; and tidal volume, P = 0.036) and serum TBARS level at admission (P = 0.013), the cut-off value of serum TBARS level at admission was 762.3 µmol/L (sensitivity 100% and specificity 90.0%). In this study, respiratory function (maximal inspiratory pressure, maximal expiratory pressure, and tidal volume) at the time of extubation can be useful optimal clinical guidelines for weaning and extubation attempts in patients with acute cervical SCI. Serum TBARS level at admission can be a useful predictor for severity in acute cervical SCI patients. Level of Evidence: 3.

The role of blink reflex R1 latency as an electrophysiological marker in diabetic distal symmetrical polyneuropathy.

OBJECTIVE: Studies showed a relatively prolonged blink R1 latency in patients with diabetic distal symmetrical polyneuropathy (DSPN) compared to that without DSPN. We tested the hypothesis that blink R1 latency would provide a diagnostic alternative to nerve conduction studies (NCS) in DSPN and act as a marker of the severity of NCS abnormalities in DSPN. METHOD: A total of 109 patients with type 2 diabetes underwent blink reflex studies and NCS. We used the composite amplitude scores of nerve conductions (CAS), which consisted of motor (tibial, peroneal and ulnar) and sensory (sural and ulnar) amplitudes for estimating the severity of NCS. RESULTS: Patients with DSPN had longer blink R1, R2, and contralateral R2 latencies (P < 0.0001, P = 0.001, and P = 0.031, respectively) and higher CAS (P < 0.0001). Area under curve on receiver operating characteristic curve analysis in diagnosing occurrence of DSPN in blink R1 latency was 0.772 (P < 0.0001). Multiple linear regression analysis showed that blink R1 latency was independently associated with CAS. CONCLUSION: Blink R1 latency may be valuable in auxiliary diagnosis and in determining the severity of NCS abnormalities in DSPN. SIGNIFICANCE: Blink R1 latency can be added as a supplemental marker of severity of NCS in DSPN, especially if the patient's sural amplitudes has a floor effect.

Sural nerve sensory response in diabetic distal symmetrical polyneuropathy.

INTRODUCTION: The sural sensory nerve action potential (SNAP) amplitude is a measure of the number of axons. We tested the hypothesis that sural SNAP amplitude can be used as a marker in screening, severity evaluation, and follow-up of diabetic distal symmetrical polyneuropathy (DSPN). METHODS: Patients with type 2 diabetes underwent nerve conduction studies and were followed for 6 years. Composite amplitude scores (CASs) were determined to evaluate DSPN severity. RESULTS: Sural SNAP amplitudes were negatively correlated with CAS (r = -.790, P < .0001), and changes in sural SNAP amplitudes were negatively correlated with those of CAS after controlling for follow-up duration (r = -.531, P = .028). DISCUSSION: When a patient's baseline sural SNAP amplitude is above zero, it can be used as one measure of DSPN in screening, severity evaluation, and follow-up. However, if the patient's sural SNAP value is zero, CAS can be used as a follow-up measure.

Neuropsychiatric symptoms in Parkinson's disease: association with caregiver distress and disease severity.

OBJECTIVES: The condition of caregivers is important to the quality of care received by people with Parkinson's disease (PD), especially at the late disease stages. This study addresses the distress placed on caregivers by participants' neuropsychiatric symptoms at different stages of PD in Taiwan. METHODS: This prospective study enrolled 108 people with PD. All participants were examined with the Unified Parkinson's Disease Rating Scale (UPDRS), Neuropsychiatric Inventory (NPI), Mini-Mental State Examination (MMSE), Cognitive Abilities Screening Instrument (CASI), and Clinical Dementia Rating (CDR) scale. Caregiver distress was measured using the Neuropsychiatric Inventory Caregiver Distress Scale (NPI-D). Statistical analysis was used to explore the PD-related factors that contribute to caregiver distress. RESULTS: The mean follow-up interval in the 108 PD participants were 24.0 ± 10.2 months with no participant lost to follow-up due to death. NPI-distress (the sum of NPI caregiver distress scale across the 12 domains of the NPI) was positively correlated with NPI-sum (the total score across the 12 domains of the NPI) (r = 0.787, p < 0.001), CDR (r = 0.403, p < 0.001), UPRDS (r = 0.276, p = 0.004), and disease duration (r = 0.246, p = 0.002), but negatively correlated with CASI (r = -0.237, p = 0.043) and MMSE (r = -0.281, p < 0.001). Multiple linear regression analysis showed that only NPI-sum and disease duration were independently correlated with NPI-distress. CONCLUSION: The disease duration and NPI-sum are independent predictors of caregiver distress in Taiwanese populations with PD. Early detection and reduction of neuropsychiatric symptoms in people with PD can help decrease caregiver distress.

Serial plasma DNA levels as predictors of outcome in patients with acute traumatic cervical spinal cord injury.

BACKGROUND: Acute traumatic cervical spinal cord injury (SCI) is a leading cause of disability in adolescents and young adults worldwide. Evidence from previous studies suggests that circulating cell-free DNA is associated with severity following acute injury. The present study determined whether plasma DNA levels in acute cervical SCI are predictive of outcome. METHODS: In present study, serial plasma nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) levels were obtained from 44 patients with acute traumatic cervical SCI at five time points from day 1 to day 180 post-injury. Control blood samples were obtained from 66 volunteers. RESULTS: Data showed a significant increase in plasma nDNA and mtDNA concentrations at admission in SCI patients compared to the control group. Plasma nDNA levels at admission, but not plasma mtDNA levels, were significantly associated with the Japanese Orthopaedic Association (JOA) score and Injury Severity Score in patients with acute traumatic cervical SCI. In patients with non-excellent outcomes, plasma nDNA increased significantly at days 1, 14 and 30 post-injury. Furthermore, its level at day 14 was independently associated with outcome. Higher plasma nDNA levels at the chosen cutoff point (> 45.6 ng/ml) predicted poorer outcome with a sensitivity of 78.9% and a specificity of 78.4%. CONCLUSIONS: These results indicate JOA score performance and plasma nDNA levels reflect the severity of spinal cord injury. Therefore, the plasma nDNA assays can be considered as potential neuropathological markers in patients with acute traumatic cervical SCI.

α-1-Acid Glycoprotein Concentration as an Outcome Predictor in Adult Patients with Sepsis.

BACKGROUND: α-1-Acid glycoprotein (AGP) is an acute-phase protein that plays a role in first-line defense against infection and is therefore elevated in sepsis. We tested the hypothesis that AGP levels increase initially in sepsis and decrease after antimicrobial therapy and that these levels may predict treatment outcomes. METHODS: AGP, biomarkers widely used in clinical practice, and maximum 24-h acute physiology and chronic health evaluation (APACHE)-II scores upon emergency department (ED) admission were prospectively evaluated and compared. We further examined changes in AGP concentrations 1, 4, and 7 days after admission and determined the value of AGP that may be used to accurately and reliably predict the prognosis in patients with sepsis. RESULTS: Mechanical ventilation, white blood cell (WBC) counts, C-reactive protein (CRP) and lactate levels, maximum 24-h APACHE-II scores, and AGP concentrations were significantly higher upon admission in patients with sepsis who died. AGP and lactate concentrations were also significantly higher in non-survivors than in survivors on days 1, 4, and 7. As indicated by the stepwise logistic regression model analysis and area under the curve analysis, AGP was the best prognostic indicator, and the cut-off value for predicting fatality was 1307 µg/mL, and any increase 1-ng/mL in AGP concentration would increase the fatality rate by 0.5%. CONCLUSION: Based on our observations, AGP may be a good prognostic predictor in patients with sepsis. In addition, serial AGP levels meet the requirements for predicting outcomes in patients with sepsis.

Adjunctive statin therapy reduces intracranial hemorrhage and 1-year mortality in patients with atrial fibrillation after acute ischemic stroke: A population-based epidemiological study from Taiwan.

BACKGROUND: Atrial fibrillation (AF)-related stroke causes severe disability and poor prognosis. Adjunctive statin therapy has been recommended for atherosclerotic-related stroke but not AF-related stroke. This study investigated the effects of statin in AF patients who experienced acute ischemic stroke. METHODS: Data from patients with AF experiencing first-ever ischemic stroke between 2001 and 2010 were collected from the Taiwan National Health Insurance Research Database and categorized into non-statin and statin groups. The statin group was further divided into pre-stroke statin (those who began statin therapy before stroke) and post-stroke statin (those who began statin therapy after stroke) groups. The risks for recurrent ischemic stroke, coronary artery disease (CAD), intracranial hemorrhage (ICH), and 1-year mortality were compared among the groups. RESULTS: A total of 43,242 patients were in the non-statin, 2858 in the pre-stroke statin and 4640 in post-stroke statin groups. Comparing the risk for recurrent stroke and CAD among the three groups, the pre-stroke statin and post-stroke statin groups did not exhibit a significant difference compared with the non-statin group. In terms of ICH risk, the statin group had a lower risk for ICH (odds ratio [OR] 0.79, 95% confidence interval [CI] 0.68-0.90; p = 0.0007) compared with the non-statin group. The overall 1-year mortality in both statin subgroups was lower than that in the non-statin group (pre-stroke statin, OR 0.55 [95% CI 0.49-0.61]; p < 0.0001 versus post-stroke statin, OR 0.53 [95% CI 0.48-0.58]; p < 0.0001). CONCLUSIONS: Statin therapy reduced the risk of ICH and 1-year mortality in AF patients who experienced acute ischemic stroke.

Long-term effects of surgical treatment on baroreflex function in patients with obstructive sleep apnea: an 18-month follow-up.

OBJECTIVE: Depressed baroreflex sensitivity (BRS) is reported in obstructive sleep apnea (OSA). Improvement of BRS short-term after surgical treatment is also reported. We tested the hypothesis that surgical treatment not only improves clinical outcomes, but also improves BRS after 18 months. METHODS: Cardiovascular autonomic tests, polysomnography (PSG), and biochemical testing were prospectively evaluated in 54 OSA patients at three time points (preoperatively, 6 months and 18 months postoperatively) and compared with 20, age- and body mass index (BMI)-matched, healthy controls. RESULTS: The BRS increased after surgical treatment at 18-month follow-up, with results similar to the healthy control. Additionally, average O2, mO2 <90% (% per night), and lowest O2 showed an increase after surgical treatment at the 18-month follow-up. CONCLUSIONS: Besides improvement in clinical outcomes, depressed BRS in OSA patients is reversible and these patients have the potential for total recovery of baroreflex function after 18 months of treatment.

HbA1C Variability Is Strongly Associated With the Severity of Cardiovascular Autonomic Neuropathy in Patients With Type 2 Diabetes After Longer Diabetes Duration.

BACKGROUND: Variability in the glycated hemoglobin (HbA1c) level is associated with a higher risk of microvascular complications in patients with type 2 diabetes. We tested the hypothesis that HbA1c variability is not only strongly associated with the presence but also the degree of severity of cardiovascular autonomic neuropathy (CAN) in patients with long diabetes durations (more than 10 years). METHODS: For each patient, the intrapersonal mean, standard deviation (SD), and coefficient of variation (CV) for HbA1c were calculated using all measurements obtained 3 years before the study. We constructed the composite autonomic scoring scale (CASS) as a measure of the severity of cardiovascular autonomic functions. Stepwise logistic regression and linear regression analyses were performed to evaluate the presence of CAN and the influence of independent variables on the mean CASS, respectively. RESULTS: Those with CAN had a higher mean age, a higher low-density lipoprotein cholesterol (LDL-C), HbA1c-SD, HbA1c-CV, mean HbA1c, and index HbA1c, higher prevalence of retinopathy as the underlying disease, and lower high-density lipoprotein (HDL) levels. Stepwise logistic regression showed that HbA1c-SD and retinopathy were risk factors that were independently associated with the presence of CAN. Mean HbA1c, HbA1c-CV, HbA1c-SD, and index HbA1c were positively correlated with mean CASS, and a multiple linear regression analysis revealed that HbA1c-SD was independently associated with the mean CASS. CONCLUSION: HbA1c variability is strongly associated with not only the presence but also the degree of severity of CAN. A longitudinal study is required to confirm whether controlling blood glucose level is effective in reducing CAN progression.