Effectiveness of question prompt lists in patients with breast cancer: A randomized controlled trial.

OBJECTIVES: To evaluate the effectiveness of a question prompt list (QPL) in decision self-efficacy, decision-making participation, patient-physician communication, decisional conflict or regret, and health status in patients with breast cancer. METHODS: A total of 240 patients with breast cancer were randomly assigned to a QPL group or control group (n = 120 each). The intervention and control groups received an additional educational QPL booklet and routine care, respectively. RESULTS: The intervention group exhibited significant improvements in decision self-efficacy, perceived patient-physician interactions, and patient-physician communication compared with the control group. Multilevel modeling analyses revealed significant group-time interaction effects on decision self-efficacy (ß = 9.99, P < 0.01), perceived patient-physician interactions (ß = 8.10, P < 0.01), patient-physician communication (ß = 5.02, P < 0.01), and anxiety status (ß = -3.78, P < 0.05). The QPL intervention exerted more favorable effects than routine care, with repeated measurements of the same patients and the data of patients under the care of the same surgeons accounted for. CONCLUSIONS: The QPL intervention exerted multidimensional effects on decision-making outcomes among patients with breast cancer. PRACTICAL IMPLICATIONS: Clinicians can integrate a QPL into routine care for patients with breast cancer.

Afamin expression in breast cancer.

BACKGROUND: Breast cancer is a collection of molecularly and clinically distinct neoplastic disease. Recent research has shown the information regarding gene expression in breast cancer could be beneficial in the designing of an optimal treatment plan and may also provide with prognostic information. The creation of tissue microarrays (TMA) allows for the rapid immunohistochemical analysis of thousands of tissue samples in parallel with minimal damage to the original blocks. This study was designed with the application of tissue microarray (TMA) to analyze the afamin status in breast cancer with the hope of elucidating the possible relationship between afamin expressions and breast cancer. METHODS: Archival tissue specimens from 106 patients with primary invasive breast cancer were analyzed for afamin expression by immunhistochemical staining with TMA. Results were compared to clinicopathologic data by multivariate analysis. RESULTS: TNM stage has shown significant relationship to the overall 5-year survival rate. However, afamin expression was not significantly related to overall five-year survival. CONCLUSION: Immunohistochemical staining with TMA was convenient and feasible for analyzing afamin expression status in breast cancer. Our preliminary results show that afamin expression showed no significant prognostic value in breast cancer.

The "right" way is not always popular: comparison of surgeons' perceptions during laparoscopic cholecystectomy for acute cholecystitis among experts from Japan, Korea and Taiwan.

BACKGROUND: Generally, surgeons' perceptions of surgical safety are based on experience and institutional policy. Our recent pilot survey demonstrated that the acceptable duration of surgery and criteria for open conversion during laparoscopic cholecystectomy (LC) vary among workplaces. METHODS: A web-based survey was distributed to 554 expert LC surgeons in Japan, Korea, and Taiwan. The questionnaire covered LC experience, safety measures and recognition of landmarks, decision-making regarding conversion to open/partial cholecystectomy and the implications of this decision. Overall responses were compared among nations, and then stratified by LC experience level (lifetime cases 200-499, 500-999, and ≥1,000). RESULTS: The response rate was 92.6% (513/554); 67 surgeons with ≤199 LCs were excluded, and responses from 446 surgeons were analyzed. We observed significant differences among nations on almost all questions. Differences that remained after stratification by LC experience were on questions related to acceptable duration of surgery, adoption rates of intraoperative cholangiography, the "critical view of safety" technique, identification of Rouvière's sulcus, recognition of the SS-Inner layer theory, and intraoperative judgment to abandon conventional LC. CONCLUSIONS: Even among experts, surgeons' perceptions during LC are workplace-dependent. A novel grading system of surgical difficulty and standardized LC procedures are paramount to generate high-level evidence.

What are the appropriate indicators of surgical difficulty during laparoscopic cholecystectomy? Results from a Japan-Korea-Taiwan multinational survey.

BACKGROUND: Serious complications continue to occur in laparoscopic cholecystectomy (LC). The commonly used indicators of surgical difficulty such as the duration of surgery are insufficient because they are surgeon and institution dependent. We aimed to identify appropriate indicators of surgical difficulty during LC. METHODS: A total of 26 Japanese expert LC surgeons discussed using the nominal group technique (NGT) to generate a list of intraoperative findings that contribute to surgical difficulty. Thereafter, a survey was circulated to 61 experts in Japan, Korea, and Taiwan. The questionnaire addressed LC experience, surgical strategy, and perceptions of 30 intraoperative findings listed by the NGT. RESULTS: The response rate of the survey was 100%. There was a statistically significant difference among nations regarding the duration of surgery and adoption rate of safety measures and recognition of landmarks. The criteria for conversion to an open or subtotal cholecystectomy were at the discretion of each surgeon. In contrast, perceptions of the impact of 30 intraoperative findings on surgical difficulty (categorized by factors related to inflammation and additional findings of the gallbladder and other intra-abdominal factors) were consistent among surgeons. CONCLUSIONS: Intraoperative findings are objective and considered to be appropriate indicators of surgical difficulty during LC.

The kinetic expression of lipopolysaccharide-binding protein and CD14 gene in obstructive jaundice.

BACKGROUND: Binding lipopolysaccharide (LPS) with high-affinity, lipopolysaccharide-binding protein (LBP) and CD14 lower the threshold stimulatory concentrations of LPS dramatically and enhance the rate of cytokine production markedly. This study aimed to investigate the kinetic expression of LBP/CD14 and its possible relationship with tumor necrosis factor alpha (TNF-α) to better understand the pathophysiology of obstructive jaundice. MATERIALS AND METHODS: The tissues (liver, spleen, intestine, and lung) of male Sprague-Dawley rats were harvested at pre-bile duct ligation in controls and at specific time points (24, 48, 72, 96, and 120 hr) after bile duct ligation. LBP, CD14, and TNF-α mRNA expression were measured in tissues harvested from controls and at the specific time points. RESULTS: Hepatic LBP mRNA expression increased significantly at five days after bile duct ligation. CD 14 mRNA expression increased significantly after five days of bile duct ligation in liver, lung, spleen, and ileum. TNF-α mRNA expression increased significantly in all four organs (liver, lung, spleen, and ileum) after four days of bile duct ligation. CONCLUSION: Five days of bile duct ligation upregulated CD 14 mRNA expression in liver, lung, spleen, and ileum and increased TNF-α mRNA expression simultaneously in the liver, lung, spleen, and ileum. In addition, five days of bile duct ligation also upregulated LBP mRNA expression in the liver and increased hepatic TNF-α mRNA expression simultaneously. The kinetic expressions of LBP and CD 14 in obstructive jaundice are intriguing and further evaluation is warranted.

Intrathecal miR-183 delivery suppresses mechanical allodynia in mononeuropathic rats.

Members of the miR-183 family are unique in that they are highly abundant in sensory organs. In a recent study, significant downregulation was observed for miR-96 and miR-183 in the L5 dorsal root ganglion (DRG) 2 weeks after spinal nerve ligation (SNL). In this study, we focused on miR-183, which is the most regulated member of the miR-183 family, to look at the specific role on neuropathic pain. Persistent mechanical allodynia was induced with the L5 SNL model in 8-week-old male Sprague-Dawley rats. Paw withdrawal thresholds in response to mechanical stimuli were assessed with Von Frey filaments. Expression of miR-183 in the L5 DRG was assessed with quantitative real-time polymerase chain reaction (qPCR) analysis. Lentivirions expressing miR-183 were injected intrathecally into SNL rats. Changes in mechanical allodynia were assessed with Von Frey filaments. In addition, changes in the predicted target genes of miR-183 were assessed with qPCR. L5 SNL produced marked mechanical allodynia in the ipsilateral hindpaws of adult rats, beginning at postoperative day 1 and continuing to day 14. L5 SNL caused significant downregulation of miR-183 in adult DRG cells. Intrathecal administration of lentivirions expressing miR-183 downregulated SNL-induced increases in the expression of Nav1.3 and brain-derived neurotrophic factor (BDNF), which correlated with the significant attenuation of SNL-induced mechanical allodynia. Our results show that SNL-induced mechanical allodynia is significantly correlated with the decreased expression of miR-183 in DRG cells. Replacement of miR-183 downregulates SNL-induced increases in Nav1.3 and BDNF expression, and attenuates SNL-induced mechanical allodynia.

An evaluation of fatty acid-CoA ligase 4 in breast cancer.

BACKGROUND: Fatty acid-CoA ligase 4 (FACL4) has been detected in various types of tumors. However, there is still very limited information about the role of FACL4 in breast cancer. Tissue microarray (TMA) technique analyzes thousands of specimens in a parallel fashion with minimal damage to the original blocks. This study was designed with the application of TMA to analyze the FACL4 status in breast cancer. MATERIALS AND METHODS: Archival tissue specimens from 102 patients with primary invasive breast cancer were selected and FACL4 expression was analyzed by immunhistochemical staining with TMA. The data of primary tumor staging, age, estrogen receptor status, lymph node status, histological grading and TNM staging were also collected. RESULTS: As shown my multivariate analysis, TNM stage was significantly related to the overall five-year survival rate. Nevertheless, FACL4 expression failed to have any significant relationship to overall five-year survival. CONCLUSION: Immuno-histochemical staining with TMA was convenient and feasible for the analysis of FACL4 expression status in breast cancer. Our preliminary results showed that FACL4 expression had no significant prognostic value in breast cancer.

Pulsed radiofrequency reduced complete Freund's adjuvant-induced mechanical hyperalgesia via the spinal c-Jun N-terminal kinase pathway.

Pulsed radiofrequency (PRF) treatment involves the pulsed application of a radiofrequency electric field to a nerve. The technology offers pain relief for patients suffering from chronic pain who do not respond well to conventional treatments. We tested whether PRF treatment attenuated complete Freund's adjuvant (CFA) induced inflammatory pain. The profile of spinal c-Jun N-terminal kinases (JNKs) phosphorylation was evaluated to elucidate the potential mechanism. Injection of CFA into the unilateral hind paw of rats induced mechanical hyperalgesia in both the ipsilateral and contralateral hind paws. We administered 500-kHz PRF treatment in 20-ms pulses, at a rate of 2 Hz (2 pulses per second) either to the sciatic nerve in the mid-thigh, or to the L4 anterior primary ramus just distal to the intervertebral foramen in both the CFA group and no-PRF group rats. Tissue samples were examined at 1, 3, 7, and 14 days following PRF treatments. Behavioral studies showed that PRF applied close to the dorsal root ganglion (DRG) significantly attenuated CFA-induced mechanical hyperalgesia compared to no-PRF group (P < .05). And western blotting revealed significant attenuation of the activation of JNK in the spinal dorsal horn compared to no-PRF group animals (P < .05). Application of PRF close to DRG provides an effective treatment for CFA-induced persistent mechanical hyperalgesia by attenuating JNK activation in the spinal dorsal horn.

Epigenetic histone methylation regulates transforming growth factor ß-1 expression following bile duct ligation in rats.

BACKGROUND: Multiple mechanisms contribute to the liver fibrosis following cholestasis. Recent research has focused on the role of transforming growth factor ß-1 (TGF-ß1) in the progression of fibrosis. The aim of our study is to examine the role of epigenetic chromatin marks, such as histone H3 lysine methylation (H3Kme), in bile duct ligation (BDL)-induced TGF-ß1 gene expression in rat liver. METHODS: Time course of methylated-histone H3 and SET7/9 recruitment were determined by chromatin immunoprecipitation in livers from BDL rats on days 1, 4, 9 and 14. Levels of TGF-ß1 and SET7/9 were determined by western blots. The effect of SET7/9 knockdown on BDL-induced expression of TGF-ß1, serum enzymes and liver collagen content was studied in vivo. RESULTS: Results showed that BDL increased the expression of the TGF ß-1. Increased levels of active chromatin marks (H3K4me1, H3K4me2, and H3K4me3) and decreased levels of repressive marks (H3K9me2 and H3K9me3) in TGF-ß1 promoter accompanied the changes in expression of the TGF ß-1. BDL also increased expression of the H3K4 methyltransferase SET7/9 and recruitment to the promoter. SET7/9 gene knockdown with siRNAs significantly attenuated BDL-induced TGF-ß1 gene expression, serum enzymes and liver collagen content. CONCLUSIONS: Taken together, these results show the functional role of epigenetic chromatin histone H3Kme in BDL-induced TGF-ß1 expression. Pharmacologic and other therapies that reverse these modifications could have potential hepatoprotective effects for BDL-induced cirrhosis.

Pulsed radiofrequency treatment attenuates increases in spinal excitatory amino acid release in rats with adjuvant-induced mechanical allodynia.

Excitatory amino acids (EAAs) play a critical role in the development of peripheral tactile and thermal hypersensitivity after the induction of paw inflammation in rats. We used a spinal microdialysis model to examine the effect of complete Freund's adjuvant (CFA)-induced inflammation on the spinal release of EAAs and assessed the antinociceptive effect of pulsed radiofrequency (PRF). CFA was injected into the plantar surface of the left hind paw to induce inflammation. Either the sciatic nerve of adult CFA rats in the mid-thigh, or the L4 anterior primary ramus just distal to the intervertebral foramen was treated with PRF (20 ms, 500 kHz pulses) at a rate of 2 Hz and a maximum temperature of 42°C. Concentrations of amino acids in the dialysate from the spinal microdialysis catheter and mechanical paw withdrawal threshold were determined to evaluate the analgesic effect of PRF. An intraplantar injection of CFA induced a significant release of glutamate, aspartate, and citrulline for 7 days. The behavior tests showed that PRF administered to the anterior ramus, just distal to the intervertebral foramen, significantly reduced mechanical allodynia, and microanalysis showed a significant suppression of EAAs and citrulline release. The antiallodynic effect of PRF was observed the day following CFA injection and maintained for 7 days. We showed that PRF administered adjacent to the dorsal root ganglion suppresses the release of EAAs, which may account for the PRF antiallodynic properties observed in adjuvant-induced inflammation.

An evaluation of focal adhesion kinase in breast cancer by tissue microarrays.

BACKGROUND: Many studies have shown that focal adhesion kinase (FAK) is a positive regulator of tumor progression and invasion. However, there is still very limited information about the role of FAK in breast cancer. Tissue microarrays (TMA) can analyze thousands of tissue samples in a parallel fashion with minimal damage to the origin block. This study was designed with the application of TMA to analyze the FAK status in breast cancer. PATIENTS AND METHODS: Archival tissue specimens from 98 patients with primary invasive breast cancer were selected and FAK expression was analyzed by immunohistochemical staining with TMA. The data of primary tumor staging, age, estrogen receptor status, lymph node status, histological grading and TNM staging were also collected. RESULTS: There were four patients (4.0%) with grade 1 expression in FAK, 41 patients (41.8%) with grade 2 expression in FAK and 53 patients (54.2%) with grade 3 expression in FAK. There was no significant relationship between FAK expression and age, estrogen receptor status, histological grading, primary tumor staging, lymph node status and TNM stage. By multivariate analysis, the TNM stage was found to be significantly related to the overall five-year survival rate (p<0.00001). CONCLUSION: Immunohistochemical staining with TMA is a convenient and feasible method. Unfortunately, our preliminary results fail to show meaningful prognostic value of FAK in breast cancer. A larger prospective study is warranted for further evaluation.

Yes-associated protein is not an independent prognostic marker in breast cancer.

BACKGROUND: The development of tissue microarray (TMA) technology has provided the opportunity to perform analyses of tissue samples on a large scale in an uniform fashion. This study was designed with the use of TMA to explore the Yes-associated protein (YAP) status in breast cancer. PATIENTS AND METHODS: YAP expression in tumor and tumor-free samples from 94 patients with primary breast cancer was analyzed by TMA. The clinicopathological data for age, estrogen receptor status, histological grading and TNM staging were also collected. RESULTS: There were 29 patients (30.8%) with 1(+) expression, in YAP, 59 patients (62.8%) with 2(+) expression and 6 (6.4%) with 3(+) expression. There was no significant relationship between YAP expression and the other clinicopathological variables. By multivariate analysis, YAP expression failed to produce any significant relationship with the overall survival rate. CONCLUSION: YAP expression is not an independent prognostic factor in patients with breast cancer.

An evaluation of prognostic value of death-associated protein kinase 1 in breast cancer.

BACKGROUND: The benefit of tissue microarray (TMA) is its capability to analyse large numbers of tissue samples in a uniform fashion. This study was designed to evaluate the capability of TMA for analyzing the status of death-associated protein kinase 1 (DAPK1) in breast cancer patient and to explore its potential in the management of breast cancer. PATIENTS AND METHODS: Over a 60-month period, tissue specimens of 99 patients with primary invasive breast cancer were selected. Tissue microarray (TMA) was applied to detect the DAPK1 expression. The data for the other clinicopathologic variables, including age, histological grading, estrogen receptor status and TNM staging were also recorded. RESULTS: Tumor in 11 patients (11.1%) scored 1 for DAPK1 expression, 55 patients (55.6%) scored 2 and 33 (33.3%) scored 3. We found no obvious link between DAPK1 expression and age, histologic grading, primary tumor staging, lymph node status, estrogen receptor and TNM stage. TNM staging was found to be significantly linked to the overall five-year survival rate through multivariate analysis. CONCLUSION: DAPK1 expression did not show any meaningful value in predicting outcome for patients with breast cancer.

Noninvasive positive pressure ventilation in the management of post-thyroidectomy tracheomalacia.

BACKGROUND: Post-thyroidectomy tracheomalacia is a rare but complicated problem. It has often been treated with tracheostomy or prolonged endotracheal intubation. However, noninvasive positive pressure ventilation (NPPV) has been successfully employed with increasing frequency in patients with respiratory failure from other causes. In the present study we describe the use of NPPV in the management of respiratory distress in patients with post-thyroidectomy tracheomalacia. METHODS: All 606 patients who underwent thyroidectomy in Chung Gung Memorial Hospital - Kaohsiung Medical Center, Taiwan, from January 2009 to August 2010 were reviewed. If tracheomalacia was diagnosed intraoperatively, the patients were left intubated and taken to the intensive care unit (ICU) (n = 5). If tracheomalacia was diagnosed in the recovery room (stridor and airway compromise not from other causes), the patient was reintubated promptly and taken to the ICU (n = 4). When subsequently re-extubated in the ICU (24-72 h later), NPPV was used to treat recurrent stridor and airway compromise. RESULTS: A total of nine patients (1.5 %) were diagnosed with post-thyroidectomy tracheomalacia, five intraoperatively and four postoperatively. The patients were intubated with an endotracheal tube and then taken to the ICU. After early re-extubation in the ICU, three of the patients with intraoperatively diagnosed tracheomalacia were found not to have respiratory problems, whereas the other six patients developed stridor and airway compromise, which resolved immediately with the initiation of NPPV. Hemoglobin oxygen saturation on pulse oximetry was also elevated. No further respiratory support was required and no complications occurred in these patients. CONCLUSIONS: Noninvasive positive pressure ventilation is effective and appears safe in the management of stridor and airway compromise following early extubation in patients with post-thyroidectomy tracheomalacia.

Clustered microcalcifications of intermediate concern detected on digital mammography: ultrasound assessment.

To report our experience with targeted-ultrasound in assessing 142 cases with clustered microcalcifications of intermediate concern detected on digital mammography. All cases had histopathologically-proven microcalcifications within the biopsied or surgical specimens. There were 30%[43/142] breast cancers and 70%[99/142] benign lesions. Only 26%[37/142] of clustered microcalcifications were identified on targeted-ultrasound and other findings including negative study (n = 33), anechoic ducts or cysts (n = 70), dilated ducts with echogenic content (n = 13) and hypoechoic nodules (n = 26). There was no statistical difference of the frequency of negative ultrasound between benign and malignant microcalcifications (P = 0.071). However, only 7.1%[5/70] cases with anechoic ducts or cysts were proven to be breast cancer. The frequencies of depiction of dilated ducts with echogenic foci or hypoechoic nodules were significantly higher for malignant microcalcifications (P < 0.001). Ultrasound was significantly more sensitive for the identification of malignant cases but biopsy of clustered microcalcifications is still warranted when targeted-ultrasound revealed negative findings.

GADD45A protects against cell death in dorsal root ganglion neurons following peripheral nerve injury.

A significant loss of neurons in the dorsal root ganglia (DRG) has been reported in animal models of peripheral nerve injury. Neonatal sensory neurons are more susceptible than adult neurons to axotomy- or nerve growth factor (NGF) withdrawal-induced cell death. To develop therapies for preventing irreversible sensory cell loss, it is essential to understand the molecular mechanisms responsible for DRG cell death and survival. Here we describe how the expression of the growth arrest- and DNA damage-inducible gene 45α (GADD45A) is correlated with neuronal survival after axotomy in vivo and after NGF withdrawal in vitro. GADD45A expression is low at birth and does not change significantly after spinal nerve ligation (SNL). In contrast, GADD45A is robustly up-regulated in the adult rat DRG 24 hr after SNL, and this up-regulation persists as long as the injured fibers are prevented from regenerating. In vitro delivery of GADD45A protects neonatal rat DRG neurons from NGF withdrawal-induced cytochrome c release and cell death. In addition, in vivo knockdown of GADD45A expression in adult injured DRG by small hairpin RNA increased cell death. Our results indicate that GADD45A protects neuronal cells from SNL-induced cell death.

Cortactin in breast cancer: analysis with tissue microarray.

BACKGROUND: Tissue microarray (TMA) allows the rapid immunohistochemical analysis of thousands of tissue samples in a parallel fashion. This study was designed to analyze the cortactin status in breast cancer using TMA and to investigate the relationship of cortactin status to breast cancer biology. PATIENTS AND METHODS: Archival tissue specimens from 99 patients with primary invasive breast cancer were selected. The cortactin expression was analyzed by TMA. Age, estrogen receptor status, histological grading and TNM staging data were also collected. RESULTS: There were 23 patients (23.2%) with low (+) expression of cortactin, 60 patients (60.6%) with intermediate (++) expression and 16(16.2%) with strong (+++) expression. There was no significant relationship between cortactin expression and age, histological grading, primary tumor staging, lymph node status, estrogen receptor and TNM stage. By multivariate analysis, estrogen receptor status and TNM staging were found to be significantly related to the overall five-year survival rate. CONCLUSION: Cortactin expression failed to demonstrate a prognostic value for patients with breast cancer.

Cellular changes in hepatocytes and intestinal endothelium after hepatoduodenal ligament occlusion and protective effects of caspase inhibition.

INTRODUCTION: Hepatic vascular control is used by many surgeons to prevent massive hemorrhage during hepatectomy. However, this may carry a risk of ischemic damage to the hepatocytes. Another major drawback of intraoperative occlusion of the hepatoduodenal ligament is portal stasis with resultant intestinal congestion which may cause adverse effects on the intestinal functions. CD44 is a transmembrane glycoprotein present in many types of epithelial cells. By mediating the attachment of dividing crypt cells to the basal lamina via hyaluronan, CD44 is considered to play a role in maintaining the intestinal villus integrity. Apoptosis is a pathway of cell death orchestrated by a family of proteases called caspases. ZVAD-fmk is a cell-permeable irreversible inhibitor of caspase and might block the processing of many caspases. This study is designed with the purpose to evaluate the impact of intraoperative occlusion of the hepatoduodenal ligament on hepatocyte and intestine functions and also to evaluate the potential influence of ZVAD-fmk on the hepatocyte and intestine functions. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomized to 5 groups. Group 1(C) underwent sham operation. Group 2 (HDL30) underwent occluding the hepatoduodenal ligament by for 30 minutes. Group 3 (HDL 15) underwent occluding the hepatoduodenal ligament by for 15 minutes, releasing for 5 minutes, underwent occlusion for another 15 minutes. Group 4 (ZHDL30) first received ZVAD-fmk, then underwent occluding the hepatoduodenal ligament by for 30 minutes. Group 5 (ZHDL15) first received ZVAD-fmk, then underwent occluding the hepatoduodenal ligament for 15 minutes, releasing for 5 minutes, underwent occlusion for another 15 minutes. After removing the temporary occlusion, liver tissue and proximal jejunum were harvested. Hepatocyte and intestine apoptosis were quantitated using the TUNEL method. CD 44 status of jejunum were determined by immunohistochemical staining. RESULTS: Hepatocyte apoptosis was significantly increased in group (HDL30) and group (HDL15) when compared with group (C). ZVAD-fmk effectively attenuated this phenomenon in both groups. There was no significant difference between group (HDL30) and group (HDL15). Jejunal apoptosis was significantly increased in group (HDL30) and group (HDL15) when compared with group (C). ZVAD-fmk effectively attenuated this phenomenon in both groups. There was no significant difference between group (HDL30) and group (HDL15). CD44 expression on jejunum was significantly increased in group (HDL30) and group (HDL15) when compared with group (C). ZVAD-fmk failed to effectively diminish this phenomenon. CONCLUSION: Occlusion of the hepatoduodenal ligament significantly increased both hepatocyte and jejunal apoptosis and pretreatment with ZVAD-fmk could effectively diminish such phenomenon. CD44 expression on jejunum was also significantly increased by intraoperative occlusion of the hepatoduodenal ligament, yet pretreatment with ZVAD-fmk failed to show significant effect on such phenomenon.

Gene transfer of IGF1 attenuates hepatocellular apoptosis after bile duct ligation.

BACKGROUND: Cholestasis occurs in a wide variety of human liver diseases, and hepatocellular injury is an invariant feature of cholestasis, causing liver dysfunction and inflammation, promoting fibrogenesis, and ultimately leading to liver failure. Insulin-like growth factor 1 (IGF1) acts in an autocrine and paracrine manner to promote glucose utilization, using phosphatidylinositol 3 kinase (PI3 K)/Akt, the downstream glycogen synthase kinase 3ß (GSK3ß), and anti-apoptotic pathways. This study investigated whether gene transfer of IGF1 could attenuate hepatocellular injury after bile duct ligation in rats. MATERIALS AND METHODS: Experiments were performed in 80 male Sprague-Dawley rats. Thirty minutes after bile duct ligation, hydrodynamics-based gene transfection with IGF1 plasmid via rapid tail vein injection. The rats were randomly divided into the following four groups: sham operated; BDL treated with pCMV-IGF1 gene; BDL treated with vehicle for pCMV-LacZ gene; and BDL only. RESULTS: IGF1 expression in liver after a single administration of IGF-1 plasmid was demonstrated. Liver function index, including serum alanine aminotransferase and aspartate aminotransferase, were significantly reduced in IGF1 gene transfer rats. We determined the mechanism of IGF1 gene transfer after BDL in terms of activation of Akt, inhibition of GSK3ß, and blockage of caspase-9 cleavage. Furthermore, hepatocyte stellate cell activation was markedly inhibited in IGF1 gene-treated rats. Apoptosis was significantly attenuated by IGF1 gene therapy. CONCLUSIONS: This study demonstrated that gene transfer of IGF1 could attenuate hepatocellular apoptosis and injury after bile duct ligation in rats.