Chung-Ching Chio

Neurological improvement after cranioplasty - analysis by transcranial doppler ultrasonography

Cranioplasty can improve neurological status in patients with skull bone defects. The mechanism of postoperative improvement in neurologic status might be increased cerebral blood flow (CBF) velocity due to elimination of the effects of atmospheric pressure. Between May 2001 and June 2002, 13 patients (8 men and 5 women; average age, 46 years; range, 21-65 years) were studied. Postoperative changes in neurological status and blood flow velocity were examined and compared using transcranial Doppler (TCD) sonography. The mean interval between craniectomy and cranioplasty was 122.3+/-100.4 days. The mean interval between cranioplasty and performance of TCD examination was 15.2+/-2.8 days. The results showed significant improvements after cranioplasty in GCS, arm muscle power, and Barthel Index. While the CBF velocities tended to increase after cranioplasty, only the increase in the non-lesion side middle cerebral artery (MCA) was statistically significant. The interval from decompressive craniectomy to cranioplasty and neurological status change before and after cranioplasty was significantly negatively correlated. We conclude that cranioplasty can improve neurological status, and it should be performed as earlier as edema has resolved.

Human umbilical cord blood-derived CD34+ cells may attenuate spinal cord injury by stimulating vascular endothelial and neurotrophic factors.

Human umbilical cord blood-derived CD34+ cells were used to elucidate the mechanisms underlying the beneficial effects exerted by cord blood cells in spinal cord injury (SCI). Rats were divided into four groups: (1) sham operation (laminectomy only); (2) laminectomy + SCI + CD34− cells (5 × 105 human cord blood lymphocytes and monocytes that contained <0.2% CD34+ cells); (3) laminectomy + SCI + CD34+ cells (5 × 105 human cord blood lymphocytes and monocytes that contained ∼95% CD34+ cells); and (4) laminectomy + SCI + saline (0.3 mL). Spinal cord injury was induced by compressing the spinal cord for 1 min with an aneurysm clip calibrated to a closing pressure of 55 g. CD34 cells or saline was administered immediately after SCI via the tail vein. Behavioral tests of motor function measured by maximal angle an animal could hold to the inclined plane were conducted at days 1 to 7 after SCI. The triphenyltetrazolium chloride staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay were also conducted after SCI to evaluate spinal cord infarction and apoptosis, respectively. To elucidate whether glial cell line-derived neurotrophic factor (GDNF) or vascular endothelial growth factor (VEGF) can be secreted in spinal cord-injured area by the i.v. transplanted CD34+ cells, analysis of spinal cord homogenate supernatants by specific enzyme-linked immunosorbent assay for GDNF or immunofluorescence for VEGF was conducted. It was found that systemic administration of CD34+, but not CD34−, cells significantly attenuated the SCI-induced hind limb dysfunction and spinal cord infarction and apoptosis. Both GDNF and VEGF could be detected in the injured spinal cord after transplantation of CD34+, but not CD34−, cells. The results indicate that CD34+ cell therapy may be beneficial in reversing the SCI-induced spinal cord infarction and apoptosis and hindlimb dysfunction by stimulating the production of both VEGF and GDNF in a spinal cord compression model.

Beneficial effect of agmatine on brain apoptosis, astrogliosis, and edema after rat transient cerebral ischemia

BackgroundAlthough agmatine therapy in a mouse model of transient focal cerebral ischemia is highly protective against neurological injury, the mechanisms underlying the protective effects of agmatine are not fully elucidated. This study aimed to investigate the effects of agmatine on brain apoptosis, astrogliosis and edema in the rats with transient cerebral ischemia.MethodsFollowing surgical induction of middle cerebral artery occlusion (MCAO) for 90 min, agmatine (100 mg/kg, i.p.) was injected 5 min after beginning of reperfusion and again once daily for the next 3 post-operative days. Four days after reperfusion, both motor and proprioception functions were assessed and then all rats were sacrificed for determination of brain infarct volume (2, 3, 5-triphenyltetrazolium chloride staining), apoptosis (TUNEL staining), edema (both cerebral water content and amounts of aquaporin-4 positive cells), gliosis (glial fibrillary acidic protein [GFAP]-positive cells), and neurotoxicity (inducible nitric oxide synthase [iNOS] expression).ResultsThe results showed that agmatine treatment was found to accelerate recovery of motor (from 55 degrees to 62 degrees) and proprioception (from 54% maximal possible effect to 10% maximal possible effect) deficits and to prevent brain infarction (from 370 mm3 to 50 mm3), gliosis (from 80 GFAP-positive cells to 30 GFAP-positive cells), edema (cerebral water contents decreased from 82.5% to 79.4%; AQP4 positive cells decreased from 140 to 84 per section), apoptosis (neuronal apoptotic cells decreased from 100 to 20 per section), and neurotoxicity (iNOS expression cells decreased from 64 to 7 per section) during MCAO ischemic injury in rats.ConclusionsThe data suggest that agmatine may improve outcomes of transient cerebral ischemia in rats by reducing brain apoptosis, astrogliosis and edema.

Retinal Artery Occlusion and the 3-Year Risk of Stroke in Taiwan: A Nationwide Population-Based Study

PURPOSE To verify the association between retinal artery occlusion (RAO) and stroke with a large-scale nationwide study. DESIGN Retrospective nationwide population-based administrative database study. METHODS Data were collected from the Longitudinal Health Insurance Database 2000 (LHID2000), which contains claim data from 1 million randomly selected beneficiaries among Taiwans 23 million residents. The study cohort consisted of all patients with a diagnosis of RAO from January 1999 through December 2006 (n = 464). The control group consisted of randomly selected patients (n = 2748) matched with the study group by age, sex, date of index medical care, and comorbid hypertension. Patients were tracked from their index date for 3 years. The Kaplan-Meier method was used to compute the stroke-free survival rate. Cox proportional hazard regressions were used to compute the adjusted stroke-free survival rate after adjusting for possible confounding factors. RESULTS Ninety-one RAO patients (19.61%) and 280 controls (10.05%) had a stroke (P < .0001) during the 3-year follow-up period. Compared with the controls, the incidence rate ratios of stroke in RAO patients were 9.46 at 0-1 month, 5.57 at 1-6 months, and 2.16 at 0-3 years after RAO (P < .0001). After adjusting for age, sex, and selected comorbid disorders, the hazard ratio of having a stroke for RAO patients was still 2.07 times higher than that of controls and 3.34 times higher in the ≤60-year-old subgroup. CONCLUSIONS RAO increases the risk for subsequent stroke. Early neurologic evaluation and secondary prevention for stroke are recommended for RAO patients.

Brain Cooling-Stimulated Angiogenesis and Neurogenesis Attenuated Traumatic Brain Injury in Rats

BACKGROUND Although brain cooling has been reported to be effective in improving the outcome after traumatic brain injury (TBI) in rats, the mechanisms of brain cooling-induced neuroprotective actions remain unclear. This study was to test whether angiogenesis and neurogenesis attenuating TBI could be brain cooling stimulated. METHODS Anesthetized rats, immediately after the onset of TBI, were divided into two groups and given the brain cooling (infusing 5 mL of 4°C saline via the external jugular vein) or no brain cooling (infusing 5 mL of 37°C saline via the external jugular vein). RESULTS Brain cooling without interference with the core temperature in rats significantly attenuated TBI-induced cerebral infarction (90 mm³ vs. 250 mm³) and motor (61 degrees vs. 57 degrees maximal angle) and proprioceptive (14% vs. 42% maximal possible effect) function deficits, significantly reduced TBI-induced neuronal (24 vs. 62 neuronal-specific nuclear [NeuN]-TUNEL double-positive cells) and glial (5 vs. 35 GFAP-TUNEL double-positive cells) apoptosis (increased TUNEL-positive and caspase-3-positive cells), neuronal loss (102 vs. 66 NeuN-positive cells), and gliosis (40 vs. 66 GFAP-positive cells; 66 vs. 89 Iba1-positive cells), and significantly promoted angiogenesis (5-bromodeoxyuridine [BrdU]/endothelial cells vs. 1-BrdU/endothelial cell; 58 vs. 31 vascular endothelial growth factor-positive cells), and neurogenesis (33 vs. 14 BrdU/NeuN positive cells). CONCLUSIONS Brain cooling-stimulated angiogenesis and neurogenesis attenuated a fluid percussion TBI in rats.

Microglial activation induced by traumatic brain injury is suppressed by postinjury treatment with hyperbaric oxygen therapy.

BACKGROUND The mechanisms underlying the protective effects of hyperbaric oxygen (HBO) therapy on traumatic brain injury (TBI) are unclear. TBI initiates a neuroinflammatory cascade characterized by activation of microglia and increased production of proinflammatory cytokines. In this study, we attempted to ascertain whether the occurrence of neuroinflammation exhibited during TBI can be reduced by HBO. METHODS TBI was produced by the fluid percussion technique in rats. HBO (100% O2 at 2.0 absolute atmospheres) was then used at 1 h (HBO I) or 8 h (HBO II) after TBI. Neurobehavior was evaluated by the inclined plane test on the 72 h after TBI and then the rats were killed. The infarction area was evaluated by Triphenyltetrazolium chloride. Immunofluorescence staining was used to evaluate neuronal apoptosis (TUNEL + NeuN), microglial cell aggregation count (OX42 + DAPI), and tumor necrosis factor-alpha (TNF-α) expression in microglia cell (OX42 + TNF-α). RESULTS The maximum grasp angle in the inclined plane test and cerebral infarction of the rats after TBI were significantly attenuated by HBO therapy regardless of whether the rats were treated with HBO 1 or 8 h after TBI compared with the controls. TBI-induced microglial activation, TNF-α expression, and neuronal apoptosis were also significantly reduced by HBO therapy. CONCLUSIONS Our results demonstrate that treatment of TBI during the acute phase of injury can attenuate microgliosis and proinflammatory cytokine TNF-α expression resulting in a neuroprotective effect. Even treating TBI with HBO after 8 h had a therapeutic effect.

Agmatine-promoted angiogenesis, neurogenesis, and inhibition of gliosis-reduced traumatic brain injury in rats.

BACKGROUND The mechanisms of agmatine-induced neuroprotective effects in traumatic brain injury (TBI) remain unclear. This study was to test whether inhibition of gliosis, angiogenesis, and neurogenesis attenuating TBI could be agmatine stimulated. METHODS Anesthetized rats were randomly assigned to sham-operated group, TBI rats treated with saline (1 mL/kg, intraperitoneally), or TBI rats treated with agmatine (50 mg/kg, intraperitoneally). Saline or agmatine was injected 5 minutes after TBI and again once daily for the next 3 postoperative days. RESULTS Agmatine therapy in rats significantly attenuated TBI-induced motor function deficits (62° vs. 52° maximal angle) and cerebral infarction (88 mm vs. 216 mm), significantly reduced TBI-induced neuronal (9 NeuN-TUNEL double positive cells vs. 60 NeuN-TUNEL double positive cells) and glial (2 GFAP-TUNEL double positive cells vs. 20 GFAP-TUNEL double positive cells) apoptosis (increased TUNEL-positive and caspase-3-positive cells), neuronal loss (82 NeuN-positive cells vs. 60 NeuN-positive cells), gliosis (35 GFAP-positive cells vs. 72 GFAP-positive cells; 60 Iba1-positive cells vs. 90 Iba1-positive cells), and neurotoxicity (30 n-NOS-positive cells vs. 90 n-NOS-positive cells; 35 3-NT-positive cells vs. 90 3-NT-positive cells), and significantly promoted angiogenesis (3 BrdU/endothelial cells vs. 0.5 BrdU/endothelial cells; 50 vascular endothelial growth factor positive cells vs. 20 vascular endothelial growth factor-positive cells) and neurogenesis (27 BrdU/NeuN positive cells vs. 15 BrdU/NeuN positive cells). CONCLUSIONS Resultantly, agmatine therapy may attenuate TBI in rats via promoting angiogenesis, neurogenesis, and inhibition of gliosis.

The New Comorbidity Index for Predicting Survival in Elderly Dialysis Patients: A Long-Term Population-Based Study

Background The worldwide elderly (≥65 years old) dialysis population has grown significantly. This population is expected to have more comorbid conditions and shorter life expectancies than the general elderly population. Predicting outcomes for this population is important for decision-making. Recently, a new comorbidity index (nCI) with good predictive value for patient outcomes was developed and validated in chronic dialysis patients regardless of age. Our study examined the nCI outcome predictability in elderly dialysis patients. Methods and Findings For this population-based cohort study, we used Taiwans National Health Insurance Research Database of enrolled elderly patients, who began maintenance dialysis between January 1999 and December 2005. A total of 21,043 incident dialysis patients were divided into 4 groups by nCI score (intervals ≤3, 4–6, 7–9, ≥10) and followed nearly for 10 years. All-cause mortality and life expectancy were analyzed. During the follow-up period, 11272 (53.55%) patients died. Kaplan-Meier curves showed significant group difference in survival (log-rank: P<0.001). After stratification by age, life expectancy was found to be significantly longer in groups with lower nCI scores. Conclusion The nCI, even without the age component, is a strong predictor of mortality in elderly dialysis patients. Because patients with lower nCI scores may predict better survival, more attention should paid to adequate dialysis rather than palliative care, especially in those without obvious functional impairments.

Umbilical Cord Blood-Derived CD34+ Cells Improve Outcomes of Traumatic Brain Injury in Rats by Stimulating Angiogenesis and Neurogenesis

Human umbilical cord blood cells (HUCBCs) have been shown to be beneficial in reducing neurological deficits in rats with brain fluid percussion injury (FPI). This study aimed to assess the basic mechanisms underlying the neuroprotective effects of HUCBC-derived cluster of differentiation 34-positive (CD34+) cells. Rats were divided into three major groups: (i) sham-operated controls; (ii) FPI rats treated with phosphate-buffered saline (PBS); (iii) FPI rats treated with 0.2%, 50%, or 95% CD34+ cells (in 5 × 105 cord blood lymphocytes and monocytes). Intravenous (IV) administration of 0.3 ml of PBS, 0.2% CD34+ cells, 50% CD34+ cells, or 95% CD34+ cells was conducted immediately after FPI. It was found that 4 days post-FPI, CD34+ cells could be detected in the ischemic brain tissues for 50% CD34+ cell- or 95% CD34+ cell-treated FPI rats, but not for the PBS-treated FPI rats or the 0.2% CD34+ cell-treated FPI rats. CD34+ cell (0.2%)-treated FPI rats or PBS-treated FPI rats displayed neurological and motor deficits, cerebral contusion and apoptosis [e.g., increased numbers of both TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling)-positive cells and caspase-3-positive cells], and activated inflammation (e.g., increased serum levels of tumor necrosis factor-α). FPI-induced neurological motor dysfunction, cerebral contusion and apoptosis, and activated inflammation could be attenuated by 50% CD34+ or 95% CD34+ cell therapy. In addition 50% or 95% CD34+ cell therapy but not PBS or 0.2% CD34+ cell therapy significantly promoted angiogenesis (e.g., increased numbers of both vasculoendothelial growth factor-positive cells and 5-bromodeoxyuridine (BrdU)-endothelial double-positive cells), neurogenesis (e.g., increased numbers of both glial cell line-derived neurotrophic factor-positive cells and BrdU/neuronal nuclei double-positive cells) in the ischemic brain after FPI, and migration of endothelial progenitor cells from the bone marrow. Our data suggest that IV administration of HUCBC-derived CD34+ cells may improve outcomes of FPI in rats by stimulating both angiogenesis and neurogenesis.

EFFECT OF BRAIN COOLING ON BRAIN ISCHEMIA AND DAMAGE MARKERS AFTER FLUID PERCUSSION BRAIN INJURY IN RATS

Although systemic cooling had recently been reported as effective in improving the neurological outcome after traumatic brain injury, several problems are associated with whole-body cooling. The present study was conducted to test the effectiveness of brain cooling without interference with the core temperature in rats after fluid percussion traumatic brain injury (TBI). Brain dialysates ischemia (e.g., glutamate and lactate-to-pyruvate ratio) and injury (e.g., glycerol) markers before and after TBI were measured in rats with mild brain cooling (33°C) and in the sham control group. Brain cooling was accomplished by infusion of 5 mL cold saline via the external jugular vein under general anesthesia. The weight loss was determined by the difference between the first and third day of body weight after TBI. The maximum grip angle in an inclined plane was measured to determine motor performance, whereas the percentage of maximal possible effect was used to measure blockade of proprioception. The triphenyltetrazolium chloride staining procedures were used for cerebral infarction assay. As compared with those of the sham-operated controls, the animals with TBI had higher values of extracellular levels of glutamate, lactate-to-pyruvate ratio, and glycerol in brain and intracranial pressure, but lower values of cerebral perfusion pressure. Brain cooling adopted immediately after TBI significantly attenuated the TBI-induced increased cerebral ischemia and injury markers, intracranial hypertension, and cerebral hypoperfusion. In addition, the TBI-induced cerebral infarction, motor and proprioception deficits, and body weight loss evaluated 3 days after TBI were significantly attenuated by brain cooling. We successfully demonstrate that brain cooling causes attenuation of TBI in rats by reducing cerebral ischemia and injury resulting from intracranial hypertension and cerebral hypoperfusion. Because jugular venipuncture is an easy procedure frequently used in the emergency department, for preservation of brain function, jugular infusion of cold saline may be useful in resuscitation for trauma patients.