Effect of follow-up raloxifene therapy after denosumab discontinuation in postmenopausal women.

Follow-up raloxifene therapy after denosumab discontinuation resulted in a decrease in bone mass to the pre-denosumab levels and a rebound increase of bone turnover markers. The decrease in lumbar bone mineral density was particularly evident when the body mass index was low, there were previous vertebral fractures, or lumbar bone mineral density before denosumab administration was low. INTRODUCTION: Selective estrogen receptor modulators may be an alternative to bisphosphonates for treating rebound resorption after discontinuing denosumab. This study aimed to investigate the effects of follow-up raloxifene therapy after denosumab discontinuation in postmenopausal women. METHODS: This retrospective observational study included 61 patients who received 12-month follow-up raloxifene therapy after denosumab discontinuation. The primary endpoint was the bone mineral density change. The secondary endpoints were the changes in bone turnover markers and the incidence of new vertebral fractures. RESULTS: Raloxifene administration for 12 months after denosumab discontinuation resulted in a significantly lower bone mineral density at all sites compared to the level at 6 months after the last denosumab treatment (lumbar spine, - 5.48%; femoral neck, - 2.95%; total hip, - 3.52%; all, p < 0.001). The decrease in lumbar bone mineral density was particularly evident when the body mass index was low, there were previous vertebral fractures, or lumbar bone mineral density before denosumab administration was low. Marked increases in the bone turnover markers from baseline were noted after switching to raloxifene. However, no new vertebral fractures occurred during raloxifene treatment. CONCLUSIONS: Follow-up raloxifene therapy after denosumab discontinuation resulted in a decrease in bone mass to the pre-denosumab levels and a rebound increase of bone turnover markers. Therefore, raloxifene administered sequentially after denosumab discontinuation was not effective in preventing rebound phenomenon.

Quality characteristics of yogurts fermented with short-chain fatty acid-producing probiotics and their effects on mucin production and probiotic adhesion onto human colon epithelial cells.

Probiotics can ferment nondigestible carbohydrates and produce short-chain fatty acids (SCFA; acetate, propionate, and butyrate) in the human colon. In this study, the levels of SCFA were determined in the following yogurts fermented with different combinations of probiotics: (1) cocultures of Streptococcus thermophilus and Lactobacillus bulgaricus (control, C); (2) S. thermophilus, L. bulgaricus, and Bifidobacterium bifidum (C-Bb); (3) S. thermophilus, L. bulgaricus, and Lactobacillus acidophilus (C-La); and (4) S. thermophilus, L. bulgaricus, and Lactobacillus gasseri (C-Lg). Results showed that the acetate levels were significantly higher in C-Bb, C-La, and C-Lg yogurts than in C yogurt. Fermentation and physicochemical characteristics of all yogurts were identical. Treatment of mucus-secreting colon epithelial cells (HT29-MTX) with C-Bb, C-La, and C-Lg yogurt supernatants resulted in an increase in the expression of MUC2 and CDX2 and the production of mucin proteins. The adhesion of probiotics onto HT29-MTX cells increased following treatment with C-Bb, C-La, and C-Lg yogurt supernatants. Our data suggest that a yogurt diet rich in acetate improves the protective function of the intestinal epithelium.

Short communication: Effects of moringa extract on adhesion and invasion of Escherichia coli O55 in bovine mammary epithelial cells.

The objective of this study was to evaluate the antibacterial activities of extract derived from moringa leaves. In particular, the effect of moringa extract (Mor) on adhesion and invasion of Escherichia coli O55, Enterococcus faecalis, Staphylococcus simulans, and Serratia liquefaciens was evaluated in bovine mammary epithelial cells (MAC-T). Broth microdilution method, minimum inhibitory concentration and minimum bactericidal concentration assays, adhesion and invasion assays, and real-time PCR were performed. The minimum inhibitory concentration and minimum bactericidal concentration of Mor ranged from 12.5 to 50 mg/mL on 18 out of 27 tested isolates. Treatment of E. coli O55 with Mor (100 and 200 µg/mL) inhibited the adhesion and invasion on MAC-T cells via downregulation of adhesion factors (i.e., papC, f17c-A, and eaeA). Also, when MAC-T cells were pretreated with Mor (200 µg/mL, 12 h) and incubated with E. coli O55, Enterococcus faecalis, Staphylococcus simulans, or Serratia liquefaciens, both E. coli O55 and Enterococcus faecalis showed a significant decrease in adhesion and invasion. Staphylococcus simulans exhibited decreased adhesion and increased invasion. Serratia liquefaciens showed increased adhesion and decreased invasion. In addition, Mor increased mRNA expression of antioxidant enzymes (e.g., heme oxygenase-1, NAD(P)H:quinone oxidoreductase-1, and thioredoxin reductase 1) in MAC-T cells. In conclusion, 12.5 to 50 mg/mL of Mor exhibited antibacterial activity against 18 out of 27 tested isolates. Also, pretreatment of 200 µg/mL of Mor to MAC-T cells modulated adhesion and invasion of E. coli O55 and other mastitis-associated pathogens. Furthermore, Mor increased antioxidant capacities in MAC-T cells, but further in vivo studies are needed.

Role of tumour location and surgical extent on prognosis in T2 gallbladder cancer: an international multicentre study.

BACKGROUND: In gallbladder cancer, stage T2 is subdivided by tumour location into lesions on the peritoneal side (T2a) or hepatic side (T2b). For tumours on the peritoneal side (T2a), it has been suggested that liver resection may be omitted without compromising the prognosis. However, data to validate this argument are lacking. This study aimed to investigate the prognostic value of tumour location in T2 gallbladder cancer, and to clarify the adequate extent of surgical resection. METHODS: Clinical data from patients who underwent surgery for gallbladder cancer were collected from 14 hospitals in Korea, Japan, Chile and the USA. Survival and risk factor analyses were conducted. RESULTS: Data from 937 patients were available for evaluation. The overall 5-year disease-free survival rate was 70·6 per cent, 74·5 per cent for those with T2a and 65·5 per cent among those with T2b tumours (P = 0·028). Regarding liver resection, extended cholecystectomy was associated with a better 5-year disease-free survival rate than simple cholecystectomy (73·0 versus 61·5 per cent; P = 0·012). The 5-year disease-free survival rate was marginally better for extended than simple cholecystectomy in both T2a (76·5 versus 66·1 per cent; P = 0·094) and T2b (68·2 versus 56·2 per cent; P = 0·084) disease. Five-year disease-free survival rates were similar for extended cholecystectomies including liver wedge resection versus segment IVb/V segmentectomy (74·1 versus 71·5 per cent; P = 0·720). In multivariable analysis, independent risk factors for recurrence were presence of symptoms (hazard ratio (HR) 1·52; P = 0·002), R1 resection (HR 1·96; P = 0·004) and N1/N2 status (N1: HR 3·40, P < 0·001; N2: HR 9·56, P < 0·001). Among recurrences, 70·8 per cent were metastatic. CONCLUSION: Tumour location was not an independent prognostic factor in T2 gallbladder cancer. Extended cholecystectomy was marginally superior to simple cholecystectomy. A radical operation should include liver resection and adequate node dissection.

ANTECEDENTES: En el cáncer de vesícula biliar, la ubicación del tumor subdivide el estadio T2 en tumores con invasión del lado peritoneal y del lado del hígado (T2a y T2b). Para los tumores que invaden el lado peritoneal (T2a) se sugiere que se puede obviar la resección hepática sin que ello comprometa el pronóstico. Sin embargo, este argumento no ha sido validado. El estudio tuvo como objetivo investigar el valor pronóstico de la localización del tumor en el cáncer de vesícula biliar T2 y establecer la extensión adecuada de la resección quirúrgica. MÉTODOS: Se recogieron los datos clínicos de pacientes que se sometieron a cirugía por cáncer de vesícula biliar en 14 hospitales de Corea, Japón, Chile y Estados Unidos. Se realizaron análisis de la supervivencia y de los factores de riesgo. RESULTADOS: Se dispuso de datos de 937 pacientes para ser evaluados. La tasa de supervivencia global libre de enfermedad a los 5 años fue del 70,6%, y las de T2a y T2b del 74,5% y 65,5% (P = 0,028). Con respecto a la resección hepática, la colecistectomía extendida presentó una tasa mejor de supervivencia libre de enfermedad a los 5 años que la colecistectomía simple (73,0% versus 61,5%, P = 0,012). La tasa de supervivencia libre de enfermedad a los 5 años fue marginalmente mejor para la colecistectomía extendida que para la colecistectomía simple tanto en T2a (76,5% versus 66,1%, P = 0,094) como en T2b (68,2% versus 56,2%, P = 0,084). Las tasas de supervivencia libre de enfermedad a los 5 años no fueron diferentes entre la resección hepática en cuña y la segmentectomía S4b+S5 (74,1% versus 71,5%, P = 0,720). En el análisis multivariable, los factores de riesgo independientes para la recidiva fueron la presencia de síntomas (cociente de riesgos instantáneos, hazard ratio, HR 1,52, P = 0,002), la resección R1 (HR 1,96, P = 0,004) y el estadio N1/N2 (N1 HR 3,40, P < 0,001; N2 HR 9,56, P < 0,001). El 70,8% de las recidivas eran metastásicas. CONCLUSIÓN: La localización del tumor no fue un factor pronóstico independiente en el cáncer de vesícula biliar T2. La colecistectomía extendida fue marginalmente superior que la colecistectomía simple. La cirugía radical debe incluir una resección hepática y una linfadenectomía adecuada.

Comparative study of new autologous material, bone-cartilage composite graft, for ossiculoplasty with Polycel® and Titanium.

OBJECTIVE: Ossiculoplasty is a surgical procedure that recreates sound transmission of the middle ear in conductive hearing loss. Various materials have been used for ossicular reconstruction, but the most ideal material for ossiculoplasty remains controversial. The purpose of this study was to introduce a novel method of autologous ossiculoplasty, bone-cartilage composite graft (BCCG) and to compare its surgical results with different types of ossiculoplastic prostheses. STUDY DESIGN: A retrospective study was performed in a tertiary referral centre. METHODS: Data of 275 patients who received ossiculoplasty using the three different materials of BCCG, Polycel® and titanium were analysed according to type of ossiculoplasty: partial or total ossicular replacement prosthesis (PORP or TORP). Hearing results, complication rates and clinical parameters including age, sex, past history, preoperative diagnosis and surgery type were compared among different groups. RESULTS: Ossiculoplasty with BCCG showed satisfactory hearing outcomes and the lowest complication rate among the three different materials. In particular, its extrusion rate was 0%. CONCLUSION: We propose that the BCCG technique is a useful alternative method for ossiculoplasty, with proper patient selection.

Exploring Bacterial Carboxylate Reductases for the Reduction of Bifunctional Carboxylic Acids.

Carboxylic acid reductases (CARs) selectively reduce carboxylic acids to aldehydes using ATP and NADPH as cofactors under mild conditions. Although CARs attracts significant interest, only a few enzymes have been characterized to date, whereas the vast majority of CARs have yet to be examined. Herein the authors report that 12 bacterial CARs reduces a broad range of bifunctional carboxylic acids containing oxo-, hydroxy-, amino-, or second carboxyl groups with several enzymes showing activity toward 4-hydroxybutanoic (4-HB) and adipic acids. These CARs exhibits significant reductase activity against substrates whose second functional group is separated from the carboxylate by at least three carbons with both carboxylate groups being reduced in dicarboxylic acids. Purified CARs supplemented with cofactor regenerating systems (for ATP and NADPH), an inorganic pyrophosphatase, and an aldo-keto reductase catalyzes a high conversion (50-76%) of 4-HB to 1,4-butanediol (1,4-BDO) and adipic acid to 1,6-hexanediol (1,6-HDO). Likewise, Escherichia coli strains expressing eight different CARs efficiently reduces 4-HB to 1,4-BDO with 50-95% conversion, whereas adipic acid is reduced to a mixture of 6-hydroxyhexanoic acid (6-HHA) and 1,6-HDO. Thus, our results illustrate the broad biochemical diversity of bacterial CARs and their compatibility with other enzymes for applications in biocatalysis.

Sequential delivery of BMP-2 and BMP-7 for bone regeneration using a heparinized collagen membrane.

To investigate the effect of the sequential delivery of bone morphogenetic proteins BMP-2 and BMP-7 on bone regeneration in rat calvarial defects (40 Sprague-Dawley rats, 8mm defect size), all animals were treated with a hydroxyapatite (HA)/tricalcium phosphate (TCP) bone graft covered with a collagen membrane. The experimental groups were as follows: (1) control group: unmodified collagen (no treatment); (2) BMP-2 group: 5 µg of BMP-2; (3) hep-BMP-7 group: 5 µg BMP-7 chemically bound to heparinized collagen; and (4) BMP-2/hep-BMP-7 group: 2.5 µg BMP-7 bound to heparinized collagen and subsequently treated with 2.5 µg BMP-2. Defect healing was examined at 2 and 8 weeks after surgery. The BMP-2 group showed the largest new bone area at week 2 (29.3 ± 7.3%; P = 0.009); new bone areas in the hep-BMP-7 and BMP-2/hep-BMP-7 groups were similar (11.8 ± 3.4% and 12.9 ± 5.71%, respectively; P = 0.917). After 8 weeks, the BMP-2/hep-BMP-7 group showed the largest new bone area (43.3 ± 6.2%), followed by the BMP-2 and hep-BMP-7 groups (P = 0.013). Accordingly, in comparison with single deliveries of BMP-2 and BMP-7, sequential delivery of BMP-2 and BMP-7 using a heparinized collagen membrane significantly induced new bone formation with a smaller quantity of BMP-2 in rat calvarial defects.

The prognostic value of pretreatment of systemic inflammatory responses in patients with urothelial carcinoma undergoing radical cystectomy.

BACKGROUND: Systemic inflammatory response (SIR) is important in the relationship between the tumour, the host, and outcome in cancer patients. However, limited data exist regarding the prognostic significance of SIR in bladder cancer. We investigate the utility of pretreatment SIR in patients with urothelial carcinoma undergoing radical cystectomy. METHODS: The study cohort consisted of 419 patients with a median follow-up of 37.7 months. The SIRs used for each described prognostic nomogram are consistent with previously published data: C-reactive protein, albumin, white cell count, neutrophil count, lymphocyte count, and platelet count. Primary end point was disease-specific survival (DSS) and overall survival (OS) after surgery. Cox regression models were used to determine the time to disease-specific and overall mortality. Multivariate regression coefficients of the predictors were used to develop nomograms for predicting 5-year DSS and OS probability. RESULTS: Multivariate Cox regression analyses revealed that albumin, lymphocyte count, and platelet count were significantly associated with a significantly increased risk for death from bladder cancer. The nomograms including each index were developed to predict the probability of 5-year DSS and OS after radical cystectomy. The C statistics were 77.8% and 77.3%, respectively, and exceeded the 2002 AJCC (72.0% and 70.3%, respectively). In the decision curve analyses, the nomograms including SIR demonstrated higher net benefit gains compared with the models without SIR. CONCLUSIONS: Cellular components of SIR have better prognostic values compared with acute-phase protein in patients undergoing radical cystectomy for bladder cancer.

Generation of ROS by CAY10598 leads to inactivation of STAT3 signaling and induction of apoptosis in human colon cancer HCT116 cells.

Prostaglandin E2 (PGE2) has been reported to play critical roles in cell fate decision by interacting with four types of prostanoid receptors such as EP1, EP2, EP3 and EP4. The present study was aimed at investigating the effect of the EP4-specific agonist CAY10598 in human colon cancer HCT116 cells. Our study revealed that treatment with CAY10598 significantly reduced the cell viability and induced apoptosis in HCT116 cells, as evidenced by the induction of p53 and Bax, release of cytochrome c, cleavage of caspase-9, -7, and -3, and PARP, and the inhibition of Bcl-2, Bcl-xL and survivin expression. Moreover, treatment with CAY10598 diminished the phosphorylation of JAK2, leading to the attenuation of STAT3 activation in HCT116 cells. CAY10598-induced apoptosis in cells which were transiently transfected with EP4 siRNA or treated with an EP4 antagonist prior to incubation with the compound remained unaffected, suggesting an EP4-independent mechanism of apoptosis induction by CAY10598. We found that treatment with CAY10598 generated reactive oxygen species (ROS) and pretreatment of cells with N-acetyl cysteine rescued cells from apoptosis by abrogating the inhibitory effect of CAY10598 on the activation of JAK2/STAT3 signaling. In conclusion, CAY10598 induced apoptosis in HCT116 cells in an EP4-independent manner, but through the generation of ROS and inactivation of JAK2/STAT3 signaling.

Genetic variants in the CYP24A1 gene are associated with prostate cancer risk and aggressiveness in a Korean study population.

BACKGROUND: Vitamin D-deactivating enzyme CYP24A1 had controversial effects on prostate cancer risk; the genetic study also showed the controversial results. Therefore, we identified the relationships between polymorphisms in CYP24A1 and prostate cancer in a Korean cohort. METHODS: We evaluated the association between 21 single-nucleotide polymorphisms (SNPs) in the CYP24A1 and prostate cancer in Korean men (272 prostate cancers and 173 controls). BPH patients with high PSA or abnormal digital rectal examination who underwent negative prostate biopsy were enrolled in the control group. Twenty-one SNPs in the CYP24A1 were selected from the International HapMap database and the NCBI database with calculation of minor allele frequency and linkage disequilibrium, preferably including the SNPs that were nonsynonymous and located within exons. We also investigated the association between 21 SNPs in the CYP24A1 gene and known clinical characteristics, such as the PSA level, clinical stage, pathological stage and Gleason score. RESULTS: The statistical analysis suggested that five CYP24A1 sequence variants (rs2248461-odds ratio (OR): 0.63, rs2248359-OR: 0.65, rs6022999-OR: 0.65, rs2585428-OR: 0.46, rs4809959-OR: 0.52) had a significant association with prostate cancer risk after multiple comparisons by a method of false discovery rate. Logistic analyses of the CYP24A1 polymorphisms with several prostate cancer-related factors showed that several SNPs were significant: four SNPs to PSA level, three to clinical stage, two to pathological stage and two SNPs to the Gleason score. CONCLUSIONS: The results of this study suggest that some CYP24A1 gene polymorphisms might be associated with the risk of prostate cancer in Korean men. Five CYP24A1 sequence variants showed the significance to predict prostate cancer, and several SNPs of CYP24A1 gene had an important finding to predict prostate cancer-related factors. However, these results should be validated in future large-scale studies.

Knockdown of RNF2 induces apoptosis by regulating MDM2 and p53 stability.

RNF2, also known as Ring1B/Ring2, is a component of the polycomb repression complex 1. RNF2 is highly expressed in many tumors, suggesting that it might have an oncogenic function, but the mechanism is unknown. Here, we show that knockdown of RNF2 significantly inhibits both cell proliferation and colony formation in soft agar, and induces apoptosis in cancer cells. Knockdown of RNF2 in HCT116 p53(+/+) cells resulted in significantly more apoptosis than was observed in RNF2 knockdown HCT116 p53(-/-) cells, indicating that RNF2 knockdown-induced apoptosis is partially dependent on p53. Various p53-targeted genes were increased in RNF2 knockdown cells. Further studies revealed that in RNF2 knockdown cells, the p53 protein level was increased, the half-life of p53 was prolonged and p53 ubiquitination was decreased. In contrast, cells overexpressing RNF2 showed a decreased p53 protein level, a shorter p53 half-life and increased p53 ubiquitination. Importantly, we found that RNF2 directly binds with both p53 and MDM2 and promotes MDM2-mediated p53 ubiquitination. RNF2 overexpression could also increase the half-life of MDM2 and inhibit its ubiquitination. The regulation on p53 and MDM2 stability by RNF2 was also observed during the etoposide-induced DNA damage response. These results provide a possible mechanism explaining the oncogenic function of RNF2, and because RNF2 is important for cancer cell survival and proliferation, it might be an ideal target for cancer therapy or prevention.

Adipose-derived stem cell-containing hyaluronic acid/alginate hydrogel improves vocal fold wound healing.

OBJECTIVES/HYPOTHESIS: The purpose of this study was to investigate the regenerative efficacy of an injectable hyaluronic acid/mildly cross-linked alginate hydrogel (HA/ALG hydrogel) containing human adipose-derived mesenchymal stem cells (hAdMSCs) for vocal fold (VF) wound healing. STUDY DESIGN: Animal research. METHODS: HA/ALG hydrogel containing hAdMSCs was injected into the VFs of rabbits immediately after direct injury. Endoscopic evaluations were performed at 1 and 3 months after injury, and functional evaluations of mucosal vibration and viscoelastic properties were carried out posteuthanization at 3 months after injury. Histopathologic and immunohistochemical evaluations of extracellular matrix (ECM) components and of hepatocyte growth factor (HGF) activity were conducted in injured VFs. The engraftment of implanted hAdMSCs was investigated by detecting fluorescent-labeled cells. RESULTS: The administration of hAdMSCs and hAdMSCs in HA/ALG hydrogel produced better macroscopic morphologies than the injection of phosphate-buffered saline (PBS). Histologic evaluations revealed that treatment with hAdMSCs in HA/ALG produced more favorable ECM changes than hAdMSC. In particular, the treatment of hAdMSCs in HA/ALG hydrogel ameliorated excessive deposition of collagen type I and increased HGF activity in regenerating VFs. hAdMSCs in HA/ALG-treated VFs also exhibited functional improvements in viscoelastic properties. hAdMSCs in HA/ALG remained viable in recipient VFs at 1 month after transplantation, and some were observed to be fostered to differentiate into fibroblasts. CONCLUSIONS: The findings of the present study suggest that HA/ALG hydrogel is a promising biomaterial for prolonging the retention time of stem cells in VFs and for promotion of VF wound healing.

Analysis of electrical property changes of skin by oil-in-water emulsion components.

OBJECTIVES: As the 'Dry Skin Cycle' produces continuous deterioration, cosmetic xerosis (flaky, dry skin) is one of the major concerns to most consumers. The purpose of this study was to investigate the moisturizing effect of oil-in-water (O/W) emulsion components. There are numerous types of oils, waxes, polyols and surfactants used as ingredients in skincare products. However, the moisturizing effect of each ingredient and understanding each use to make an effective moisturizing products are still not well understood. METHODS: To provide answers to these questions, we investigated the moisturizing effect of widely used 41 components (four different classes) in a simple O/W emulsion using capacitance methods. 106 different single oils, and combinations of oil with oil, wax, humectants, and surfactant were formulated and tested. RESULTS: In this study, we found that most of the O/W emulsion components had hydration effects on the skin. (i) The average relative water content increase (RWCI) rate of a single oil-based emulsion was 11.8 ± 5.2% (SE) and 7.9 ± 6.0% (SE) at 3 and 6 h, respectively. (ii) An oil combination emulsion showed an average RWCI rate similar to that of a single oil-based emulsion, 12.6 ± 6.0% (SE) and 12.1 ± 6.4% (SE) at 3 and 6 h, respectively (iii) A combination of waxes with oil showed an average RWCI rate of 16 ± 5.6% (SE) and 12.4 ± 4.5% (SE) at 3 and 6 h, respectively. (iv) Humectant combinations showed the highest average RWCI rate 28 ± 7.3% (SE) and 22.2 ± 7.5% (SE) at 3 and 6 h, respectively (v) Surfactant combinations had an average RWCI of 10.8 ± 4.5% (SE) and 6.0 ± 4.0% (SE) at 3 and 6 h, respectively. CONCLUSION: Interestingly, it was difficult to find moisturizing power differences among samples in the same group. Only the humectants group showed significant differences among samples. Glycerine and urea showed significant skin hydration effects compared with other humectants. We also found a significant moisturizing effect by analysing the chemical functional groups; amide class had a higher hydration effect than betaines and disaccharides in humectants combination.

Cancer upregulated gene 2, a novel oncogene, confers resistance to oncolytic vesicular stomatitis virus through STAT1-OASL2 signaling.

We have recently found a novel oncogene, named cancer upregulated gene 2 (CUG2), which activates Ras and mitogen-activated protein kinases (MAPKs), including ERK, JNK and p38 MAPK. Because activation of these signaling pathways has previously been shown to enhance cancer cell susceptibility to oncolysis by certain viruses, we examined whether vesicular stomatitis virus (VSV) could function as a potential therapeutic agent by efficiently inducing cytolysis in cells transformed by CUG2. Unexpectedly, NIH3T3 cells stably expressing CUG2 (NIH-CUG2) were resistant to VSV because of the activation of signal transducers and activators of transcription 1 (STAT1). The result was supported by evidence showing that suppression of STAT1 with short interference RNA (siRNA) renders cells susceptible to VSV. Furthermore, 2'-5' oligoadenylate synthetase-like (OASL) 2 was the most affected by STAT1 expression level among anti-viral proteins and furthermore suppression of OASL2 mRNA level caused NIH-CUG2 cells to succumb to VSV as seen in NIH-CUG2 cells treated with STAT1 siRNA. In addition, Colon26L5 carcinoma cells stably expressing CUG2 (Colon26L5-CUG2) exhibited resistance to VSV, whereas Colon26L5 stably expressing a control vector yielded to VSV infection. Moreover, Colon26L5-CUG2 cells stably suppressing STAT1 succumbed to VSV infection, resulting in apoptosis. Taken together, we propose that VSV treatment combined with the selective regulation of genes such as STAT1 and OASL2 will improve therapeutic outcomes for CUG2-overexpressing tumors.

A dose-response study of remifentanil for attenuation of the hypertensive response to laryngoscopy and tracheal intubation in severely preeclamptic women undergoing caesarean delivery under general anaesthesia.

BACKGROUND: Remifentanil is known to attenuate the cardiovascular responses to tracheal intubation. We determined effective doses (ED(50)/ED(95)) of remifentanil to prevent the pressor response to tracheal intubation in patients with severe preeclampsia. METHODS: Seventy-five women with severe preeclampsia were randomly allocated to one of five remifentanil dose groups (0.25, 0.50, 0.75, 1.0, or 1.25 µg/kg) given before induction of anaesthesia using thiopental 5 mg/kg and suxamethonium 1.5 mg/kg. Systolic arterial pressure, heart rate and plasma catecholamine concentrations were measured. Neonatal effects were assessed by Apgar scores and umbilical cord blood gas analysis. A dose was considered effective when systolic arterial pressure did not exceed 160 mmHg for more than 1 min following tracheal intubation. RESULTS: Baseline systolic blood pressure and heart rate did not differ among the groups. The intubation-induced increases of heart rate and blood pressure were attenuated in a dose-dependent manner by remifentanil. ED(50) and ED(95) were 0.59 (95% CI 0.47-0.70) µg/kg and 1.34 (1.04-2.19)µg/kg, respectively. Norepinephrine concentrations remained unaltered following intubation but increased significantly at delivery, with no differences between the groups. Apgar scores and umbilical arterial and venous pH and blood gas values were comparable among the groups. Two women each in the 1.0 and 1.25 µg/kg groups received ephedrine for hypotension defined as systolic arterial pressure <90 mmHg. CONCLUSIONS: The ED(95) of remifentanil for attenuating the hypertensive response to tracheal intubation during induction of anaesthesia in severely preeclamptic patients undergoing caesarean delivery under general anaesthesia was 1.34 µg/kg.

Thiopental dose requirements for induction of anaesthesia and subsequent endotracheal intubation in patients with complete spinal cord injuries.

BACKGROUND: Dose requirements of thiopental depend on patient characteristics and infusion rate. We determined thiopental dose requirements for induction of anaesthesia, and the effects of remifentanil on cardiovascular and bispectral index (BIS) responses to tracheal intubation in spinal cord-injured (SCI) patients undergoing general anaesthesia. METHODS: Twenty patients with traumatic complete SCI undergoing elective surgery were enrolled. Twenty patients without SCI served as control. Anaesthesia was induced with thiopental, followed by remifentanil 1 µg/kg and rocuronium 0.8 mg/kg, and maintained with 2% sevoflurane and 50% nitrous oxide in oxygen after tracheal intubation. Thiopental was administered at a rate of 50 mg/15 s until abolition of the eyelash reflex. Thiopental doses, BIS values, systolic arterial blood pressure (SAP), heart rate (HR) and plasma catecholamine concentrations were measured. RESULTS: Total thiopental dose required to abolish the eyelash reflex based on total body weight (BW) (5.26 ± 0.87 vs. 3.91 ± 1.07 mg/kg, P < 0.001) or lean BW (6.56 ± 1.37 vs. 5.24 ± 1.36 mg/kg, P < 0.01) were significantly smaller in the SCI group than in the control. SAP was decreased by induction of anaesthesia with thiopental and remifentanil, and increased by tracheal intubation in both groups. However, the peak SAP after intubation was smaller in the SCI patients. HR increased significantly above baseline values following intubation in both groups with no significant intergroup differences. Hypertension was more frequent in the control group. Norepinephrine concentrations remained unaltered following intubation in both groups. CONCLUSIONS: These results suggest that the dose requirements of thiopental for induction of general anaesthesia and subsequent tracheal intubation are reduced in the SCI patients.

Increase of paradoxical excitement response during propofol-induced sedation in hazardous and harmful alcohol drinkers.

BACKGROUND: Paradoxical excitement response during sedation consists of loss of affective control and abnormal movements. Chronic alcohol abuse has been proposed as a predisposing factor despite lack of supporting evidence. Because alcohol and propofol have a common site of action, we postulated that paradoxical excitement responses during propofol-induced sedation occur more frequently in hazardous and harmful alcohol drinkers than in social or non-drinkers. METHODS: One hundred and ninety patients undergoing orthopaedic knee joint surgery were enrolled in this prospective and observational study. Subjects were divided into Group HD (hazardous and harmful drinkers) or Group NHD (no hazardous drinkers) according to the alcohol use disorder identification test (AUDIT). In study 1, propofol infusion was adjusted to achieve the bispectral index at 70-80 using target-controlled infusion. In study 2, the target concentration of propofol was fixed at 0.8 (study 2/Low) or 1.4 µg ml(-1) (study 2/High). Paradoxical excitement responses were categorized by intensity into mild, moderate, or severe. RESULTS: The overall incidence of paradoxical excitement response was higher in Group HD than in Group NHD in study 1 (71.4% vs 43.8%; P=0.022) and study 2/High (70.0% vs 34.5%; P=0.006) but not in study 2/Low. The incidence of moderate-to-severe response was significantly higher in Group HD of study 1 (28.6% vs 3.1%; P=0.0005) and study 2/High (23.3% vs 3.4%; P=0.029) with no difference in study 2/Low. Severe excitement response occurred only in Group HD of study 1 and study 2/High. CONCLUSIONS: Paradoxical excitement occurred more frequently and severely in hazardous and harmful alcohol drinkers than in social drinkers during propofol-induced moderate-to-deep sedation, but not during light sedation.

Dose-related attenuation of cardiovascular responses to tracheal intubation by intravenous remifentanil bolus in severe pre-eclamptic patients undergoing Caesarean delivery.

BACKGROUND: The optimal dose of remifentanil to attenuate the cardiovascular responses to tracheal intubation in pre-eclamptic patients undergoing Caesarean delivery under general anaesthesia has not been established. We compared the effects of two low doses of remifentanil on the cardiovascular responses to tracheal intubation and neonatal outcomes. METHODS: Forty-eight women with severe pre-eclampsia were randomly assigned to receive either remifentanil 0.5 µg kg⁻¹ (R0.5 group, n=24) or 1 µg kg⁻¹ (R1.0 group, n=24) over 30 s before induction of anaesthesia using thiopental 5 mg kg⁻¹ and succinylcholine 1.5 mg kg⁻¹. Systolic arterial pressure (SAP), heart rate (HR), and plasma catecholamine concentrations were measured. Neonatal effects were assessed using Apgar scores and umbilical cord blood gas analysis. RESULTS: SAP was decreased by induction of anaesthesia and increased by tracheal intubation in both groups. The peak SAP after intubation was greater in the R0.5 group than in the R1.0 group, whereas it did not exceed baseline values in either group. HR increased significantly above baseline in both groups with no significant differences between the groups. Three subjects in the R1.0 group received ephedrine due to hypotension (SAP < 90 mm Hg). Norepinephrine concentrations remained unaltered after intubation and increased significantly at delivery with no significant differences between the groups. Neonatal Apgar scores and umbilical arterial and venous pH and blood gas values were comparable between the groups. CONCLUSIONS: Both doses of remifentanil effectively attenuated haemodynamic responses to tracheal intubation with transient neonatal respiratory depression in pre-eclamptic patients undergoing Caesarean delivery under general anaesthesia. The 1.0 µg kg⁻¹ dose was associated with hypotension in three of 24 subjects.

Relationship of statins to clinical presentation and biochemical outcomes after radical prostatectomy in Korean patients.

The aim of this study was to determine whether or not statins influence biochemical recurrence (BCR) in Korean patients undergoing surgical treatment for prostate cancer. We reviewed data from 687 men who underwent radical retropubic prostatectomy and who did not receive neoadjuvant treatment. Of these patients, 87 reported the use of preoperative statins at surgery. BCR-free survival was determined after exclusion of 78 patients with lymph node metastases and/or who received immediate adjuvant treatment. Patients on statin therapy were more likely to have a co-morbid disease (P < 0.05). Mean PSA (9.6 vs 13.6 ng ml(-1), P = 0.002) and PSA density (0.27 vs 0.38 ng ml(-1) ml(-1), P<0.001) were significantly lower in patients on statins. However, in the multivariable linear regression model, statin use was not associated with a decrease in PSA. Overall BCR for the entire cohort was not significantly different between the statin and nonstatin groups. On multivariate analysis, positive surgical margin and seminal vesicle invasion were independent risk factors for BCR-free survival, whereas other variables, including statin use, were not significant in predicting the risk of BCR. Patients with positive surgical margin and seminal vesicle invasion had a 2.1- (odds ratio, 2.15; 95% confidence interval, 1.29-3.57; P = 0.003) and 2.2-fold risk (odds ratio, 2.21; 95% confidence interval, 1.25-3.89; P = 0.006) of BCR. Preoperative statin use is not associated with reduced BCR following radical prostatectomy.

Altered cardiovascular responses to tracheal intubation in patients with complete spinal cord injury: relation to time course and affected level.

BACKGROUND: We determined cardiovascular responses to tracheal intubation in relation to the time since injury in patients with different levels of spinal cord injury. METHODS: Two hundred and fourteen patients with complete cord injury were studied. They were either quadriplegics (>C7, n=71) or paraplegics (20 yr. Twenty patients with no cord injury served as controls. Systolic arterial pressure (SAP), heart rate (HR), and plasma catecholamine concentrations were determined. RESULTS: Intubation did not affect SAP in the quadriplegics regardless of the time post-injury, but it significantly increased SAP in all paraplegics. Moreover, the pressor response was enhanced in the paraplegics who were 10 yr or more since injury (P<0.05). HR increased significantly in all groups; the magnitude of the increase was less only in acute quadriplegics compared with controls. Plasma concentrations of norepinephrine increased in every group except for the quadriplegics within 4 weeks of injury. The maximum increases in SAP, HR, and norepinephrine from awake baseline values were smaller in the quadriplegics than in the paraplegics (P<0.01). CONCLUSIONS: The cardiovascular and catecholamine responses to intubation change as a function of the time elapsed and the level of the cord injury. In this study, the pressor response to tracheal intubation was abolished in the quadriplegics but not in paraplegics; indeed, it was enhanced at 10 yr or more since injury in this group.