Nucleostemin upregulation and STAT3 activation as early events in oral epithelial dysplasia progression to squamous cell carcinoma

Most low-grade oral epithelial dysplasia remains static or regress, but a significant minority of them (4–11%) advances to oral squamous cell carcinoma (OSCC) within a few years. To monitor the progression of epithelial dysplasia for early cancer detection, we investigated the expression profiles of nucleostemin (NS) and phospho-STAT3 (p-STAT3) in rodent and human samples of dysplasia and OSCCs. In a 4NQO-induced rat oral carcinogenesis model, the number and distribution of NS and p-STAT3-positive cells increased in hyperplastic, dysplastic, and neoplastic lesions compared to normal epithelium. In human samples, the NS signal significantly increased in high-grade dysplasia and poorly differentiated OSCC, whereas p-STAT3 was more ubiquitously expressed than NS and showed increased intensity in high-grade dysplasia and both well and poorly differentiated OSCC. Analyses of human dysplastic samples with longitudinally followed outcomes revealed that cells with prominent nucleolar NS signals were more abundant in low-grade dysplasia that advanced to OSCC in 2 or 3 years than those remaining static for 7–14 years. These results suggest that NS upregulation and STAT3 activation are early events in the progression of low-grade dysplasia to OSCC.     

小檗碱对培养大鼠心肌细胞胞内游离Ca2+的作用

利用Fura-2技术和AR-CM-MIC阳离子测定系统,直接观察了小檗碱对培养大鼠心肌细胞胞内[Ca²⁺]i的影响。结果显示:小檗碱可明显升高心肌细胞静息[Ca²⁺]i且具饱合性,维拉帕米和CoCl₂对其有一定的抑制作用;小檗碱与高K⁺,高Ca²⁺,去甲肾上腺素,哇巴因合用比单用上述激动剂更能明显增高[Ca²⁺]i;维拉帕米对其有抑制作用;在胞外无外Ca²⁺和无外Ca²⁺,外K⁺,外Na⁺时,小檗碱30～200μmol·L^-1仍能升高静息[Ca²⁺]i,维拉帕米只对前者有一定抑制作用。结果提示:小檗碱可能通过促胞外Ca²⁺内流和胞内Ca²⁺释放等途径有限度地增高心肌细胞内游离Ca²⁺浓度,显示强心作用。     

Anemoside A3 Enhances Cognition through the Regulation of Synaptic Function and Neuroprotection

Compounds that have the ability to both strengthen synaptic function and facilitate neuroprotection are valuable cognitive enhancers that may improve health and quality of life, as well as retard age-related cognitive deterioration. Medicinal plants are an abundant source of potential cognitive enhancers. Here we report that anemoside A3 (AA3) isolated from Pulsatilla chinensis modulates synaptic connectivity in circuits central to memory enhancement. AA3 specifically modulates the function of AMPA-type glutamate receptors (AMPARs) by increasing serine phosphorylation within the GluA1 subunit, which is a modification required for the trafficking of GluA1-containing AMPARs to synapses. Furthermore, AA3 administration activates several synaptic signaling molecules and increases protein expressions of the neurotrophin brain-derived neurotrophic factor and monoamine neurotransmitters in the mouse hippocampus. In addition to acting through AMPARs, AA3 also acts as a non-competitive NMDA receptor (NMDAR) modulator with a neuroprotective capacity against ischemic brain injury and overexcitation in rats. These findings collectively suggest that AA3 possesses a unique ability to modulate the functions of both AMPARs and NMDARs. Concordantly, behavioral studies indicate that AA3 not only facilitates hippocampal long-term potentiation but also enhances spatial reference memory formation in mice. These multifaceted roles suggest that AA3 is an attractive candidate for further development as a cognitive enhancer capable of alleviating memory dysfunctions associated with aging and neurodegenerative diseases.     

A KDEL Retrieval System for ER-Golgi Transport of Japanese Encephalitis Viral Particles

Evidence has emerged that RNA viruses utilize the host secretory pathway for processing and trafficking mature viral particles and for exiting the infected cells. Upon completing the complex assembly process, the viral particles take advantage of the cellular secretory trafficking machinery for their intracellular trafficking toward the Golgi organelle and budding or export of virions. In this study, we showed that Japanese encephalitis virus (JEV)-induced extracellular GRP78 contains no KDEL motif using an anti-KDEL-specific antibody. Overexpression of the KDEL-truncated GRP78 in the GPR78 knocked down cells significantly reduced JEV infectivity, suggesting that the KDEL motif is required for GRP78 function in the release of JE viral particles. In addition, we demonstrated the KDELR protein, an ER-Golgi retrieval system component, is associated with viral envelope proteins and is engaged in the subcellular localization of viral particles in Golgi. More importantly, accumulation of intracellular virions was observed in the KDELR knocked down cells, indicating that the KDELR protein mediated the intracellular trafficking of JE viral particles. Altogether, we demonstrated that intracellular trafficking of JE assembled viral particles was mediated by the host ER-Golgi retrieval system prior to exit by the secretory pathway.     

Chronic viral C hepatitis associated with primary biliary cirrhosis. Report of two cases

Chronic viral hepatitis C is often associated with various autoimmune disorders. We report two patients infected by genotype 1b hepatitis C virus associated with primary biliary cirrhosis. These patients had anicteric cholestasis associated with cytolysis and positivity of M2 antimitochondrial antibodies at a titre of 1/200. Liver biopsy revealed chronic hepatitis in one case and histological pattern of primary biliary cirrhosis in the other. One patient was treated by antiviral therapy; the other only by ursodesoxycholic acid because of the association with hemolytic anemia. Association between primary biliary cirrhosis and chronic viral hepatitis C is uncommon and associated with diagnostic and therapeutic challenges.     

Efficacy of short‐course lansoprazole with clarithromycin and amoxicillin in the eradication of Helicobacter pylori in South‐East Asian patients: 5‐day t.d.s. versus 7‐day b.d. treatment regimens

OBJECTIVE : To determine and compare the efficacy of 5‐day t.d.s and 7‐day b.d. treatment regimens comprising lansoprazole, clarithromycin and amoxicillin in the eradication of Helicobacter pylori. METHODS : Patients with unequivocal evidence of H. pylori infection based on histology and rapid urease tests of both antrum and corpus biopsies were recruited for the study. The study was a randomized, investigator‐blind, comparative study. Patients received either 500 mg clarithromycin t.d.s. and 500 mg amoxicillin t.d.s. for 5 days (LAC5) or 500 mg clarithromycin b.d. and 500 mg amoxicillin b.d. for 7 days (LAC7) together with 30 mg lansoprazole (both groups) daily for either 5 or 7 days, depending on the treatment group. Patients were assessed for the successful eradication of H. pylori, defined as the absence of bacteria based on histology and urease tests on both antral and corporeal biopsies, carried out at least 4 weeks after completion of the therapy. RESULTS : One hundred and eight patients were recruited for the study. In the LAC5 treatment group, four patients failed to return for follow up and in the LAC7 group, two failed to return for follow up and two were not compliant with medications. Eradication rates based on an intention‐to‐treat analysis were: 46/54 for LAC5 (85.2%; 95% CI = 72.9–93.4) and 47/54 for LAC7 (87.0%; 95% CI = 75.1–94.6). Based on a per protocol analysis, the rates were: 46/50 for LAC5 (92.0%; 95% CI = 80.8–97.8) and 47/50 for LAC7 (94.0%; 95% CI = 83.5–98.7). Both treatment regimens were convenient for patients and except for two patients in the LAC7 group, all patients reported taking 100% of all prescribed medications. The side‐effects encountered were uniformly mild and no patient discontinued treatment because of intolerance to medications. The most common side‐effects were altered taste (LAC5 64.7%; LAC7 78.8%). Diarrhea, nausea and anorexia were reported in a minority of patients. CONCLUSIONS : Both the LAC5 t.d.s. and the LAC7 b.d. treatment regimens were well tolerated by patients and were highly effective in the eradication of H. pylori.     

Human platelet antigens: HPA-1, -2, -3, -4, and -5 polymorphisms in kidney transplantation

To investigate the association between kidney transplant rejection and polymorphisms of HPA-1, -2, -3, -4, and -5, the genomic DNA of 70 renal transplant recipients and 100 healthy blood donors was analyzed by polymerase chain reaction (PCR)-SSP. The patients were classified into two groups. Group 1 included 33 HLA-identical recipients and group 2, 37 one haplo-identical recipients. Thirty-one recipients experienced an acute rejection episode (ARE): 10 in group 1 and 21 in group 2. Ten group 2 patients developed chronic allograft dysfunction (CAD). Before transplantation, five patients in group 1 were lymphocytocytotoxic antibodies (LCT) positive, among them three developed an ARE. In group 2, seven recipients were LCT positive and four had an ARE. After transplantation, 29 patients were LCT positive: 11 in group 1 and 18 in group 2, among them: 6/11 and 11/18 had an ARE. The allelic frequencies of HPA-1, -2, and -5 among patients and controls did not reveal significant differences, whereas the HPA-3a and HPA-4b alleles were significantly more frequent among patients than controls: 91.4% and 27.8% versus 76.5% and 11.5% respectively (P < .05 and P < .001). The frequency of the HPA-3b allele was increased in patients with an ARE (11.3%) and those who developed CAD (20%) compared with those not affected by these complications (6.6% and 6.4%, respectively), but the difference was not significant. The genotype distribution of HPA-1, -3, and -4 genes of GPIIb/IIIa revealed that the most frequent genotype was HPA-1a1a/3a3a/4a4a (19%) among controls and HPA-1a1a/3a3a/4a4b (31.4%) among patients. This genotype was associated with an ARE in 25.8%, namely 50% of group 1 recipients and 14.28% of group 2. The HPA-4b polymorphism of GPIIb/IIIa receptor seem to be an independent risk factor for acute allograft rejection in kidney transplantation.     

Kidney Transplantation: Charles Nicolle Hospital Experience

The aim of our retrospective study was to analyze the short- and long-term follow-up of 298 renal transplantations performed between June 1986 and May 2005. All were first transplantations except 4 cases, with 54 from cadaveric and 244 from living donors. The recipients included 196 males and 102 females of overall mean age of 31.21 ± 8.9 years (range, 16-61 years). A combination of prednisolone and azathioprine was presented for 212 patients or mycophenolate mofetil for 86 patients. Polyclonal or monoclonal antibodies were used as induction therapy in 183 cases. Cyclosporine was administered to 188 cases and tacrolimus only to 16.HLA matching was 0 mismatches (MM) in 65 cases; 1 or 2 MM in 113; 3 MM in 99; and ≥4 MM in 21. Acute tubular necrosis occurred in 45 cases. One hundred eighteen patients experienced at least 1 acute rejection episode: 102 cases (41.8%) among living and 16 (29.6%) among cadaveric kidneys donor (P = .0007). The actuarial patient and graft survival rates at 1, 5, 10, 15, and 20 years were 95.9%, 87.4%, 77.5%, 65.6%, and 60.8%, and 94.9%, 84.5%, 75.4%, 65.4%, and 53%, respectively. Sixty-three patients died and 72 patients returned to dialysis. Our results were comparable to experienced centers. However, the member of kidney transplantations does not match the increased number of patients on renal replacement therapy. It is advisable to promote obtaining organs from brain-dead donors.     

The PTPN22 C1858T (R620W) Functional Polymorphism in Kidney Transplantation

To investigate the association between kidney transplant rejection and PTPN22 (protein tyrosine phosphatase non-receptor 22) polymorphism, genomic DNA of 175 renal transplant recipients and 100 healthy blood donors were genotyped by restriction fragment length polymorphism-polymerase chain reaction. The patients were classified in two groups: G1 included 33 HLA-identical recipients and G2 included 142 with one or more HLA mismatches. Forty-nine patients developed an acute rejection episode (ARE): 8 in G1 and 41 in G2. The allelic frequencies of PTPN22 R620W revealed a significant difference between patients and controls. In fact, the W-allele was significantly more frequent in graft recipients than in blood donors (0.05 vs 0.01, P < .05). Furthermore, the frequency of this allele was increased in G1 patients with an ARE (0.188) compared with those without an ARE (0.040), but the difference was not statistically significant. Thus, we concluded that the PTPN22 W-variant allele could be involved in the susceptibility to acute allograft rejection in Tunisian kidney transplant patients.     

体外循环心脏不停跳与非体外循环冠状动脉搭桥术治疗冠状动脉三支病变的疗效

目的 探讨心肺转流(CPB)下行心脏不停跳冠状动脉搭桥术(OPBH)与非体外循环下冠状动脉搭桥术(OPCAB)治疗冠状动脉三支病变的临床效果.方法 210例单纯冠状动脉三支病变患者分为0PCAB组(105例)和OPBH组(105例),分别进行临床观察.结果 OPCAB组无一例需转成OPBH.所有患者均在心脏侧壁和后壁区域搭桥.两组人均冠状动脉远端吻合数和再血管化指数相似;手术后呼吸支持时间、胸腔引流量和输血量OPCAB组明显少于OPBH组;围手术期死亡率和并发症发生率两组比较差异无统计学意义.结论 对于低左室射血分数的患者,虽然出血和输血量较大,术后呼吸支持时间、ICU停留时间较长,但OPBH能取得与OPCAB相同的疗效.