Limitation of the validity of the homeostasis model assessment as an index of insulin resistance in Korea

Homeostasis model assessment of insulin resistance (HOMA-IR) is a less invasive, inexpensive, and less labor-intensive method to measure insulin resistance (IR) as compared with the glucose clamp test. The aim of this study was to evaluate the validity of HOMA-IR by comparing it with the euglycemic clamp test in determining IR. We assessed the validity of HOMA-IR by comparing it with the total glucose disposal rate measured by the 3-hour euglycemic-hyperinsulinemic clamp in subjects with type 2 diabetes (n = 47), impaired glucose tolerance (n = 21), and normal glucose tolerance (n = 22). There was a strong inverse correlation (r = -0.558; P < .001) between the log-transformed HOMA-IR and the total glucose disposal rate. There was moderate agreement between the 2 methods in the categorization according to the IR (weighted kappa = 0.294). The magnitude of the correlation coefficients was smaller in the subjects with a lower body mass index (BMI <25.0 kg/m2 , r = -0.441 vs BMI > or =25.0 kg/m2 , r = -0.615; P = .032), a lower HOMA-beta cell function (HOMA- beta <60.0, r = -0.527 vs HOMA- beta > or =60.0, r = -0.686; P = .016), and higher fasting glucose levels (fasting glucose < or =5.66 mmol/L, r = -0.556 vs fasting glucose >5.66 mmol/L, r = -0.520; P = .039). The limitation of the validity of the HOMA-IR should be carefully considered in subjects with a lower BMI, a lower beta cell function, and high fasting glucose levels such as lean type 2 diabetes mellitus with insulin secretory defects.     

Gonadotropin-releasing hormone activates mitogen-activated protein kinase in human ovarian and placental cells

Considering that the action of gonadotropin-releasing hormone (GnRH) may be mediated via different signaling pathways in extrapituitary tissues, in the present study we investigated the role of the human GnRH receptor (GnRHR) in activating mitogen-activated protein kinases (MAPKs), which regulate cell growth, division, and differentiation. The phosphorylation state of p44 and p42 MAPKs was examined using antibodies that distinguish phospho-p44/42 MAPK (P-MAPK, Thr²⁰²/Tyr²⁰⁴) from total p44/42 MAPK (T-MAPK, activated plus inactivated) in human ovarian and placental cells. Cell cultures were treated with various concentrations of a GnRH agonist, (D-Ala⁶)-GnRH, for 5 min. (D-Ala⁶)-GnRH stimulated a rapid activation of P-MAPK in human granulosa-luteal cells (hGLCs) and immortalized extravillous trophoblast (IEVT) cells. Interestingly, (D-Ala⁶)-GnRH treatment of ovarian cancer (OVCAR-3) and placental carcinoma (JEG-3) cells induced a biphasic regulatory pattern in P-MAPK activity. In contrast, no change of T-MAPK levels was observed following addition of the GnRH agonist in the ovarian and placental cells examined. The physiological implication of MAPK activation by GnRH in the ovarian and placental cells was also investigated. Human GLCs were treated with (D-Ala⁶)-GnRH for 24 h, and progesterone secretion was measured by an established RIA. (D-Ala⁶)-GnRH induced a significant decrease in progesterone secretion with maximum inhibition (a 45% decrease over basal level) at 10⁻⁷ M. This inhibitory effect was completely reversed by pretreatment with MAPK/ERK kinase 1 (MEK1) inhibitor (PD98059), suggesting the involvement of the MAPK pathway in hGLCs. Placental JEG-3 cells were treated with (D-Ala⁶)-GnRH for 24 h, and βhCG mRNA level was measured using Northern blot analysis. (D-Ala⁶)-GnRH stimulated the expression of βhCG mRNA to 160% of control value in JEG-3 cells. In contrast to the ovarian cells, pretreatment of JEG-3 cells with PD98059 failed to block the stimulatory effect of GnRH on βhCG mRNA level, suggesting that other signaling pathway(s) may play a more dominant role in GnRH-induced βhCG mRNA expression. To our knowledge, this is the first demonstration that (1) GnRH induces activation of the MAPK signaling pathway in normal and carcinoma cells of the human ovary and placenta, and (2) MAPK mediates the direct action of GnRH on progesterone production in hGLCs.     

皮质激素辅助治疗结核性脑膜炎的研究现状

结核性脑膜炎（tuberculous meningitis，TBM）以血脑屏障紊乱、颅内压升高和脑水肿为特征，是人型结核分枝杆菌感染最严重的类型。未经治疗死亡率达100%，治疗后死亡率约为10%，生存者中约80%有严重的神经系统后遗症。随着新增病例的不断增多，世界卫生组织（World Health Organiza-tion，WHO）在2007年的结核防治报告中提出：“要让所有结核患者都有机会得到有效的治疗。”目前尚没有明确针对TBM最佳治疗方案的临床指南。临床上主要参考肺结核的治疗方案。     

Adenomatous polyposis coli protein contains two nuclear export signals and shuttles between the nucleus and cytoplasm

Mutational inactivation of the adenomatous polyposis coli (APC) tumor suppressor initiates most hereditary and sporadic colon carcinomas. Although APC protein is located in both the cytoplasm and the nucleus, the protein domains required to maintain a predominantly cytoplasmic localization are unknown. Here, we demonstrate that nuclear export of APC is mediated by two intrinsic, leucine-rich, nuclear export signals (NESs) located near the amino terminus. Each NES was able to induce the nuclear export of a fused carrier protein. Both APC NESs were independently able to interact with the Crm1 nuclear export factor and substitute for the HIV-1 Rev NES to mediate nuclear mRNA export. Both APC NESs functioned within the context of APC sequence: an amino-terminal APC peptide containing both NESs interacted with Crm1 and showed nuclear export in a heterokaryon nucleocytoplasmic shuttling assay. Also, mutation of both APC NESs resulted in the nuclear accumulation of the full-length, approximately 320-kDa APC protein, further establishing that the two intrinsic APC NESs are necessary for APC protein nuclear export. Moreover, endogenous APC accumulated in the nucleus of cells treated with the Crm1-specific nuclear export inhibitor leptomycin B. Together, these data indicate that APC is a nucleocytoplasmic shuttle protein whose predominantly cytoplasmic localization requires NES function and suggests that APC may be important for signaling between the nuclear and cytoplasmic compartments of epithelial cells.     

The gastrointestinal tract in uremia

Gastrointestinal mucosal abnormalities ranging from edema to ulceration occur in two thirds of patients dying of uremia. Early studies suggested that uremic patients on maintenance dialysis treatment were at increased risk of peptic ulceration but more recent data indicate that this is not so. Other gastrointestinal problems reported for uremic subjects on maintenance dialysis treatment include bleeding from telangiectatic lesions, constipation, mucosal deposition of amyloid and acute pancreatitis. Nausea and vomiting are common in the uremic patient but gastric emptying studies have yielded conflicting results. Patients undergoing renal transplantation are at increased risk of development of esophagitis, complicated peptic ulcer, intestinal ulceration, and perforation as well as acute pancreatitis.     

葛根素诱导血管平滑肌细胞凋亡的实验研究

目的：观察葛根素促进人脐动脉血管平滑肌细胞凋亡的作用，探讨葛根素抑制平滑肌细胞增殖的机制。方法：分离培养人脐动脉平滑肌细胞，不同浓度葛根素与细胞孵育，TUNEL检测葛根素诱导细胞凋亡，rt-PCR实验检测促凋亡基因Bax和抗凋亡基因Bcl-XL。结果：随着葛根素浓度升高，细胞生长受抑制，TUNEL阳性细胞显著增加。rt-PCR实验发现促凋亡基因Bax随药物浓度和作用时间的增加而上升，而且Bax、Bcl-XL基因表达比例有一定升高。结论：葛根素通过调节经典的Bax、Bcl-XL通路对血管平滑肌细胞凋亡有一定诱导作用。     

老年稳定型心绞痛并高血压者抗心绞痛药物的联合应用

目的　探讨老年高血压合并稳定型心绞痛患者应用小剂量单一和多种抗心绞痛药物的短期疗效。　 方法 　 3 6例老年稳定型心绞痛合并高血压患者 (Ⅰ组 )和 3 4例稳定型心绞痛老年患者 (Ⅱ组 )口服苯磺酸氨氯地平 (络活喜 )、5 单硝异山梨醇酸酯 (德脉宁 )、倍他乐克和巯甲丙脯酸等。另 3 5例老年稳定型心绞痛患者单用德脉宁做对照组 (Ⅲ组 )。用药 2 8d后以超声心动图 (UCG)、ECG和发射型计算机断层扫描 (ECT)等评价单一和多种小剂量抗心绞痛药物的疗效。　 结果 　Ⅰ组患者心绞痛严重度降级最显著 (由 2 62级降至 1 4级 ) ,此组患者超声心动图EF % (心脏射血分数 )和ECT心肌灌注也较其余 2组有更明显提高。Ⅰ组心电图ST在服药后 3、14、2 8d与治疗前比 ,其t =2 3 4,10 94,19 0 8;前者P <0 0 5 ,后 2者均P <0 0 1,ST明显恢复。Ⅱ组也较对照组ST恢复幅度大。　 结论 　心绞痛合并高血压组老年患者在小剂量多种抗心绞痛药物合用后短期效果最好 ,表现其ST ,EF %和ECT心肌缺血和灌注均有明显恢复与提高。无高血压心绞痛组老年病人小剂量多种药物合用也较单用德脉宁疗效佳。因此对有或无高血压稳定性心绞痛老年患者应提倡小剂量多种药物联合抗心绞痛 ,则有利于治疗和防止严重心脏事件的发生。     

Stimulation of interstitial collagenase in co-cultures of rat hepatocytes and sinusoidal cells

Although the fibrosis observed during chronic liver injury is the result of a complex process, the striking accumulation of collagen in end stage liver disease has provoked interest in the mechanisms that regulate both collagen production and degradation in the diseased liver. The present studies have examined the cell interactions that may be important in the regulation of collagen degradation. Although minimal amounts of interstitial collagenase activity were noted in cultures of normal hepatocytes and sinusoidal cells, the co-cultures of these cells in the presence of lipopolysaccharide showed a substantial increase in collagenase activity. When the hepatocytes were obtained from rats that had been treated with carbon tetrachloride in vivo, the enhanced activity seen in the co-cultures did not require the addition of lipopolysaccharide. Further characterization of this interaction suggested that the increase in collagenolytic activity was partially due to the elaboration of soluble factors by the hepatocyte, which stimulated collagenase production by the sinusoidal cell population. Elaboration of collagenase activity by the sinusoidal cells was inhibited by cycloheximide, suggesting that protein synthesis was required. The proteolytic activity was abrogated by inhibitors of metalloproteinases but not by serine or thiol proteinase inhibitors. The degradation products of type I collagen were typical of the expected products seen with vertebrate collagenases. Thus, it appears that the increased collagenolytic activity detected in this co-culture system is attributable to the production of interstitial collagenase by the sinusoidal cell population. Such cell-cell interactions may play an important role in the maintenance of normal connective tissue structure of the liver during disease processes.     

Liposome-complexed adenoviral gene transfer in cancer cells expressing various levels of coxsackievirus and adenovirus receptor

Purpose Loss of coxsackievirus and adenovirus receptor (CAR) is frequently observed in malignant cancer, hampering adenoviral gene therapy approaches. Complexing adenovirus with cationic liposomes can increase adenoviral transgene expression, particularly in cells with CAR-deficiency. We investigated whether other factors such as lipid composition might be involved in determining the efficiency of liposome-complexed adenoviral gene transfer in cancer cells.Material and methods Human cancer cell lines with different expression levels of CAR were infected with a GFP transgene. The efficiency of transgene expression was assessed by determining GFP expression using FACS analysis.Results The efficiency of liposome-complexed adenoviral gene transfer was dependent on the lipid composition constituting liposomes. Polyethylene glycol (PEG)-containing liposomes were most effective in increasing liposome-complexed adenoviral gene transfer. In CAR-deficient cells, use of PEG-containing liposomes enhanced adenoviral gene transfer, whereas in CAR-expressing cells enhancement varied depending on cell type. In some CAR-expressing cells, the effect of liposome complexing was even comparable to that in CAR-deficient cells. Increased adenoviral transgene expression following complexing with PEG-containing liposomes correlated with liposome uptake in cancer cells.Conclusions Liposome-complexed adenoviral gene transfer appears to depend on lipid composition and the level of liposome uptake by cancer cells, in addition to CAR levels. Our study suggest that these multiple factors should be considered in designing liposome-complexed adenoviral vectors to improve outcomes of current adenoviral cancer gene therapies.     

Impact of matrix metalloproteinase-1 gene variations on risk of acute coronary syndrome

OBJECTIVES: This case-control study was conducted to investigate whether genetic variations in the matrix metalloproteinase-1 gene promoter were related to risk of acute coronary syndrome (ACS). DESIGN AND METHODS: 222 patients with ACS and 191 normal controls were examined by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism. RESULT: A significantly higher frequency of AA genotype of -519A/G polymorphism was observed in ACS patients than in the controls (P<0.001). The relative risk of ACS in patients carrying A allele of -519A/G polymorphism was 1.33 [P<0.001, 95% confidence interval (CI)=1.12-1.57]. Linkage disequilibrium test and haplotype analysis indicated that the AT haplotype significantly increased the risk of ACS (P=0.004, 95% CI=1.14-2.04, odds ratio=1.53). Compared with the AT haplotype, the GT haplotype was associated with a reduced occurrence of ACS (P<0.001, 95% CI=0.36-0.70, odds ratio=0.51). CONCLUSION: Our findings suggested that genetic variations in the matrix metalloproteinase-1 gene promoter may contribute to interindividual variability in risk of ACS, and help predict susceptible individuals.