Tsong-Hai Lee

Association of μ‐opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty

Background:  Morphine consumption after a given surgical procedure can vary considerably. Studies show that single nucleotide polymorphism involving the nucleotide position 118 at exon 1 of the μ‐opioid receptor gene (OPRM1) may play a role in mediating the effects of opioids. This study was performed to correlate the A118G polymorphism at OPRM1 with morphine consumption in patients undergoing total knee arthroplasty.

Electroporation-mediated pain-killer gene therapy for mononeuropathic rats

The relatively low expression levels achieved from transferred genes have limited the application of nonviral vectors for gene transfer into the spinal cord in vivo. Thus, the aim of this study was to evaluate the efficacy of electroporation-mediated pro-opiomelanocortin (POMC) gene therapy for neuropathic pain using an animal model of chronic constrictive injury (CCI). Firstly, the optimal pulse characteristics (voltage, pulse duration, number of shocks) were investigated for in vivo electroporation-mediated gene transfer into the spinal cord. The electroporation process makes use of plasmid DNA, which expresses the POMC gene. Expression levels were evaluated in this study by Western blot. We conclude that the optimal conditions for electroporation are a pulse voltage of 200 V, 75-ms duration, 925-ms interval, for five iterations. Secondly, electroporation treatment for neuropathic pain was attempted on CCI rats using plasmid DNA that expresses the POMC gene. Intrathecal administrations of the POMC vector elevated spinal beta-endorphin levels, as manifested in a significantly elevated pain threshold for the CCI limbs. This result suggests that gene therapy for neuropathic pain using this novel technique is very efficacious, and thus shows promise for further clinical trials.

Spinal Cord Infarction in Chinese Patients

Background: The clinical presentations, MRI findings and outcomes for spinal cord infarction (SCI) are well documented in the West but scarce in the East. We investigated the clinical characteristics of SCI patients and further analyzed etiologies and prognostic factors in Chinese subjects. Methods: We reviewed all SCI patients from March 1993 to March 2007. Clinical symptoms, laboratory and imaging findings as well as outcomes were retrospectively analyzed. Results: Twenty-two patients (12 female) were identified; their mean age was 57.6 years. Nine patients (40.9%) had probable etiologies, while 13 were cryptogenic (59.1%). The primary etiologies were aortic diseases. Hypertension was the most common vascular risk factor (50%). Most patients (10/22 = 45.5%) had thoracolumbar lesions (mainly at T9–L1), while cervical lesions (9/22 = 40.9%) were the second most common (mainly at C4–C7). ‘Owl’s eyes’ signs were common with the anterior spinal artery (93.8%) and central cord infarctions (50%) but not in the posterior spinal artery or transverse spinal infarctions. After a mean follow-up of 18 months, only 10 patients (10/22 = 45%) had good outcomes (independent walking or walking with 1 aid). Conclusion: Most SCI patients had acute, monophasic symptoms, reaching nadir in <24 h. The subjects frequently had acute pain near their lesions before SCI signs/symptoms (16/22 = 72.7%). Initial severe weakness (Medical Research Council score ≤2) and a young age at onset (55 years old) are correlated with poor recovery of motor functions.

Predictors of carotid artery stenosis after radiotherapy for head and neck cancers

OBJECTIVE To study the prevalence of and risk factors associated with carotid artery stenosis (CAS) after radiotherapy (RT) for head and neck cancer. METHODS DESIGN OF STUDY Prospective, cross-sectional study. SETTING Patients recruited from a hospital Radiation-Oncology department. SUBJECTS From March 2002 to August 2006, 290 consecutive head and neck cancer patients were enrolled in this study. One hundred ninety-two of these patients had previously undergone RT (RT group) and 98 had no RT (control group). INTERVENTION After detecting CAS by carotid duplex sonography, the severity of CAS was evaluated by a bilateral plaque scoring system. MAIN OUTCOME MEASURE CAS score. RESULTS There were no differences in age or gender between the two groups. The RT group had a significantly higher plaque score than the non-irradiated group (P < .05). Multiple regression analysis of the 290 head and neck cancer patients revealed that bilateral plaque score was significantly correlated with age, hyperlipidemia, and RT. Multiple regression analysis was performed in the RT group alone with patients 41-50 years old serving as the reference group. This analysis showed that in RT patients > 50 years old, age was inversely correlated with plaque score; however, in RT patients <or= 41 years old, age was positively correlated with plaque score. CONCLUSION In head and neck cancer, the high post-treatment incidence of radiation-induced CAS indicates the importance of regular examination of the carotid duplex and early antiplatelet prophylaxis. Different age groups may require different irradiation strategies to prevent radiation-induced CAS.

Dose Titration to Reduce Dipyridamole-Related Headache

Background: Combination of low-dose aspirin and modified-release dipyridamole (ASA+MR-DP) provides a significantly increased benefit in stroke prevention over aspirin alone. However, headaches were reported in more patients receiving dipyridamole-containing agents than in those receiving placebo. We undertook a randomized, double-blind, placebo-controlled trial to evaluate which dosing regimens of ASA+MR-DP have better tolerance. Methods: This trial randomized 146 patients with a history of ischemic cerebrovascular disease into three groups: placebo (days 1–28), reduced dose (placebo on days 1–4, ASA+MR-DP once daily before bed during days 5–14, and b.i.d. on days 15–28), and regular dose (placebo on days 1–4, and ASA+MR-DP b.i.d. on days 5–28). Using Chinese diary card, headache was assessed as mean cumulated headache (Σ frequency × intensity/occurrence days × study days) over the study period, and was graded 0–4 according to Cancer Therapy Evaluation Program, Common Toxicity Criteria, Version 2.0. Results: Intent-to-treat patients after randomization was 46 in placebo group, 45, reduced dose, and 49, regular dose. Among commonly reported adverse effects, headache of any grade occurred significantly more in the regular dose group (38.8%), as compared to the other two groups (p < 0.05). Mean cumulated headache was higher (p < 0.05) in the regular dose group than in the reduced group during days 5–14. Of 27 patients who dropped out, 15 (55.6%) were due to headache, which was substantially more in regular dose (8, 53.3%), though the difference was statistically insignificant. Conclusions: Initial reduced dose treatment with ASA+MR-DP may cause fewer headaches than regular dosing, and seems better tolerated by those susceptible to phosphodiesterase inhibitor-induced headache.

Recurrent hypertensive intracerebral hemorrhage

Hypertensive intracerebral hemorrhage has been considered as a one‐time event with rare recurrence. This observation is quite different from our experience in Taiwan. We, therefore, conducted a systematic review of our series of consecutive patients with recurrent bleeding. During a 2‐year period, we encountered 47 patients with recurrent hypertensive intracerebral hemorrhage from a total of 892 consecutive patients with hypertensive hemorrhage (5.3%). There were 25 men and 22 women with a mean age of 59 ± 10 (range: 36–78) years at the onset of the first hemorrhage and 62 ± 9 (range: 39–80) years at the second hemorrhage. The median interval between 2 hemorrhages was 2 years and 4 months (range: 1 month to 8.5 years). All except one recurrent hemorrhages occurred at a site different from the previous one. Of the 38 patients admitted to our hospital for both hemorrhages only 5 were regularly treated with antihypertensive therapy. The outcome for the recurrent bleeding was grave: 26% died and 51% became totally dependent or vegetative. Recurrent hypertensive hemorrhage is not as rare as previously thought; it comprises 5.3% of our patients with hypertensive intracerebral hemorrhage. The recurrent hemorrhage, however, rarely occurs at the same location as the previous one. Uncontrolled hypertension appears to be an important risk factor for the recurrence. Control of blood pressure after the first bleeding should be attempted to prevent recurrent hemorrhage.

Central Hyperthermia in Acute Stroke

Background: Central hyperthermia is an unresolved riddle; this study tries to define its characteristics. Methods: Seventy-four previously healthy patients who developed hyperthermia (≥39°C) within 24 h after stroke onset were enrolled. The lesion sites, nature of stroke, and clinical features were studied. Results: Brainstem hemorrhage was the most common cause of hyperthermia (64%), followed by putamino-thalamus hemorrhage (24%), cerebellum hemorrhage (4%), large cortical infarct (4%), basilar artery occlusion (3%), and intraventricular hemorrhage (1%). Whatever the site of the lesion, all patients had brainstem involvement either by direct destruction or indirect compression. Three fourths of the patients reached 39°C within 12 h of stroke, and 82% arrived at the maximum within 24 h. A peculiar finding of central hyperthermia was the marked fluctuation in body temperature within a short period, which was more severe initially then decreased gradually. Leukocytosis was seen in 60%, but shift to the left was rare (1%). The prognosis was grave, nearly 70% of the patients expired within 1 month, especially those with a temperature of >41°C or those who reached 39°C within 6 h after onset of stroke, or those who had severe fluctuations in temperature. Conclusions: Central hyperthermia is characterized by rapid onset of high fever, marked temperature fluctuation and high mortality. It is likely associated with brainstem (mainly pons) damage by direct destruction or indirect compression.

Electroporative α-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation

Hepatic fibrosis represents a process of healing and scarring in response to chronic liver injury. α-Melanocyte-stimulating hormone (α-MSH) is a 13-amino-acid peptide with potent anti-inflammatory effects. We have previously demonstrated that α-MSH gene therapy protects against thioacetamide (TAA)-induced acute liver failure. Therefore, the aim of this study is to investigate whether α-MSH gene therapy possesses antihepatic fibrogenic effect. Liver fibrosis was induced by long-term TAA administration in mice. α-Melanocyte-stimulating hormone expression plasmid was delivered via electroporation after liver fibrosis was established. Our results showed that α-MSH gene therapy attenuated liver fibrosis in TAA-treated mice. Reverse transcription polymerase chain reaction revealed that α-MSH gene therapy attenuated the liver transforming growth factor-β1, collagen α1 and cell adhesion molecule mRNA upregulation. Following gene transfer, the expression of α-smooth muscle actin and cyclooxygenase-2 were both significantly attenuated. Further, α-MSH significantly increased matrix metalloproteinase (MMP), while tissue inhibitors of matrix metalloproteinase (TIMPs) were inactivated. In summary, α-MSH gene therapy reversed established liver fibrosis in mice and prevented the upregulated fibrogenic and pro-inflammatory gene responses after TAA administration. Its collagenolytic effect might be attributed to MMP and TIMP modulation. Hence, α-MSH gene therapy may be an effective therapeutic modality against liver fibrosis with potential clinical use.

The circadian rhythm controls telomeres and telomerase activity

Circadian clocks are fundamental machinery in organisms ranging from archaea to humans. Disruption of the circadian system is associated with premature aging in mice, but the molecular basis underlying this phenomenon is still unclear. In this study, we found that telomerase activity exhibits endogenous circadian rhythmicity in humans and mice. Human and mouse TERT mRNA expression oscillates with circadian rhythms and are under the control of CLOCK-BMAL1 heterodimers. CLOCK deficiency in mice causes loss of rhythmic telomerase activities, TERT mRNA oscillation, and shortened telomere length. Physicians with regular work schedules have circadian oscillation of telomerase activity while emergency physicians working in shifts lose the circadian rhythms of telomerase activity. These findings identify the circadian rhythm as a mechanism underlying telomere and telomerase activity control that serve as interconnections between circadian systems and aging.

Establishment of Electronic Chart-based Stroke Registry System in a Medical System in Taiwan

To establish a prospective, real-time, self-sustainable stroke registry system, we incorporated a registry with an electronic chart to create an electronic chart-based stroke registry system in November 2006. The International Classification of Diseases Ninth Revision code (430-437) was used to auto-enroll stroke patients admitted to neurology departments. Clinical information was written by doctors, nursing information was recorded by nurses, and basic patient information was entered by administrative departments. Numerical data and the date and time of any studies were auto-downloaded from the hospital computer. In total, 212 items were auto-downloaded, including basic patient information, laboratory blood test and examination results, and the date and time of imaging and special intervention. The stroke scales (121 items, National Institutes of Health Stroke Scale, Barthel index, and modified Rankin scale) were designed to be auto-adjusted to reduce incompatibility. The 95 items with pull-down options were used to specify the contents. This registry system can be time-, labor- and money-saving with secured data accuracy.