[Effect of imatinib on the height of children with chronic myeloid leukemia in the chronic phase].

Objective: To evaluate the effect of imatinib on growth impairment in children with chronic myeloid leukemia (CML-CP) in the chronic phase. Methods: From July 2018 to July 2019, questionnaires were distributed to CML children aged <18 years at the time of diagnosis who were receiving imatinib for at least 3 months or to their parents in China. The height-for-age standard deviation score (HtSDS) and the difference of standard deviation integral (△HtSDS) were used to explore the change in height with imatinib therapy. Results: The data of 238 respondents were included; 138 (58.0% ) respondents were men. The median age at the first diagnosis of CML was 11.0 years (range, 1.4-17.9 years) , and 93 (39.0% ) respondents were at the prepuberty stage. At the time of completing the questionnaires, the median age was 15.0 years (range, 2.0-34.0 years) . The median duration of imatinib therapy was 28 months (range, 3-213 months) . Among all the respondents, the mean HtSDS when completing the questionnaires (-0.063±1.361) was significantly lower than that at the time of starting imatinib treatment (0.391±1.244) (P<0.001) . Total 71.0% respondents showed growth impairment that was more common in those starting imatinib therapy at prepubertal age than in those starting at pubertal age. Multivariate analysis showed that younger at the start of imatinib therapy (P<0.001) and longer duration of imatinib therapy (P<0.001) were significantly associated with severe growth impairment on imatinib therapy. Conclusions: Imatinib induced growth impairment in children with CML-CP. Younger the age of initiation and longer the duration of imatinib therapy, more obvious the effect of imatinib on growth impairment.

[Reliability and validity of the Chinese version on Alcohol Use Disorders Identification Test].

Objective: To assess the reliability and validity of the Chinese version on Alcohol Use Disorders Identification Test (AUDIT) among medical students in China and to provide correct way of application on the recommended scales. Methods: An E-questionnaire was developed and sent to medical students in five different colleges. Students were all active volunteers to accept the testings. Cronbach's α and split-half reliability were calculated to evaluate the reliability of AUDIT while content, contract, discriminant and convergent validity were performed to measure the validity of the scales. Results: The overall Cronbach's α of AUDIT was 0.782 and the split-half reliability was 0.711. Data showed that the domain Cronbach's α and split-half reliability were 0.796 and 0.794 for hazardous alcohol use, 0.561 and 0.623 for dependence symptoms, and 0.647 and 0.640 for harmful alcohol use. Results also showed that the content validity index on the levels of items I-CVI) were from 0.83 to 1.00, the content validity index of scale level (S-CVI/UA) was 0.90, content validity index of average scale level (S-CVI/Ave) was 0.99 and the content validity ratios (CVR) were from 0.80 to 1.00. The simplified version of AUDIT supported a presupposed three-factor structure which could explain 61.175% of the total variance revealed through exploratory factor analysis. AUDIT semed to have good convergent and discriminant validity, with the success rate of calibration experiment as 100%. Conclusion: AUDIT showed good reliability and validity among medical students in China thus worth for promotion on its use.

Inhibition of miR-141 reverses cisplatin resistance in non-small cell lung cancer cells via upregulation of programmed cell death protein 4.

OBJECTIVE: MicroRNAs are a class of essential regulators in cancer, and previous studies have shown that miR-141 is a tumor suppressor in non-small cell lung cancer (NSCLC). However, it is still unknown whether it regulates chemosensitivity. We aimed to investigate the role of miR-141 in cisplatin resistance in NSCLC cells. MATERIALS AND METHODS: MiR-141 expression in A549 and A549/DDP cell lines have been quantified by real-time PCR. Protein level of PDCD4 and caspase-3 have been determined by Western blot analysis. Drug sensitivity and apoptosis have been determined by MTT assay and TUNEL assay, respectively. Luciferase activity assay was employed to validate the relationship between 3'UTR of PDCD4 mRNA and miR-141. RESULTS: We observed that miR-141 expression was significantly up-regulated in cisplatin-resistant A549/DDP cells compared with the parental cell line A549; and PDCD4, an important apoptosis regulator, was found to be down-regulated. Luciferase activity assay and Western blot analysis confirmed that PDCD4 is a direct target of miR-141. Inhibition of miR-141 in A549/DDP cells markedly increased cisplatin sensitivity and apoptosis, which was partially abrogated by PDCD4 inhibition, indicating that PDCD4 is a functional target of miR-141 in of the regulation of cisplatin sensitivity. CONCLUSIONS: Our data showed that miR-141 participates in regulating cisplatin sensitivity in non-small lung cancer cells via PDCD4 inhibition, and suppression of miR-141 might be a therapeutic method to overcome cisplatin resistance in clinical practice.

A comparative study of single incision versus conventional laparoscopic inguinal hernia repair.

BACKGROUND: Over the past years, safety and feasibility of conventional laparoscopic inguinal hernia repair was well established. However, conventional laparoscopic hernia repair (CL) usually requires three working ports ranging from 5 to 10 mm, and each increasing port is associated with possible increasing morbidity and pain related to ports. This has led to the development of single incision laparoscopic hernia repair (SIL) which can further reduce the port-related morbidities and improve cosmetic outcomes. The aim of the study was to evaluate the safety and feasibility of SIL using both transabdominal preperitoneal (TAPP) and totally preperitoneal (TEP) approaches and compare the patients' wound satisfaction between the two groups. METHODS: This is a retrospective review of prospectively collected data. We analyzed the results of patients who underwent either CL or SIL for inguinal hernia between January 2011 and July 2012 in Pamela Youde Nethersole Eastern Hospital. Patients' demographic details, type of hernia, operative time, mesh used, and post-operative complications were compared. A telephone survey was also conducted to evaluate patients' subjective wound satisfaction. RESULTS: In total, 32 SIL and 35 CL procedures were performed in this period. The two groups were matched for age, sex, type of hernia and ASA grading. The mean operative time was significantly shorter in the CL group (52.6 vs. 62.6 min, p = 0.02). All SIL procedures were completed successfully without conversion to CL or open repair and post-operative complications such as wound infection, seroma, recurrence and chronic pain were also comparable between the two groups. As for the telephone survey, SIL groups' wound is less obvious and less detectable by others as compared to CL, but on the whole both groups of patients are very satisfied with the wound outcomes. All the SIL groups would continue with their decision on SIL and 60 % of CL group would choose SIL if they had to go back in time. CONCLUSION: Our results have shown that in experienced hands, SIL is feasible and as safe as CL. Further randomized trials should be performed to evaluate the clinical application of single incision TEP and TAPP.

Efficient delivery of connective tissue growth factor shRNA using PAMAM nanoparticles.

The aim of this study was to detect the anti-fibrosis activity of connective tissue growth factor (CTGF) small hairpin RNA (shRNA) mediated by polyamidoamine dendrimer nanoparticles in rat myocardial cell lines and myocardium. CTGF shRNAs were constructed from inverted oligonucleotides and a polyamidoamine nanoparticle vector was used to transfer shRNA into H9c2 myocardial cells and spontaneously hypertensive rats. The expression of CTGF, transforming growth factor-b1, and laminin were measured by semi-quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. pCTGF-shRNA significantly reduced CTGF upregulation induced by angiotensin II in H9c2 myocardial cells. The mRNA and protein expression of CTGF and laminin in pCTGF-shRNA-transferred spontaneously hypertensive rats decreased significantly compared to the control group and pHK-shRNA group (P < 0.05). The expression of transforming growth factor-b1 showed no significant difference among the 3 groups (P > 0.05). pCTGF-shRNA mediated by polyamidoamine can be used to successfully reduce myocardial CTGF and laminin expression, suggesting that this system can be used to improve myocardial fibrosis therapy.

Revealing the contribution of Cytochrome P450 to salt-sensitive hypertension using DNA microarray.

BACKGROUND: Salt sensitivity is an important cause of hypertension which is a major public health problem. This study aimed to investigate the contribution of Cytochrome P450 (CYP) to salt-sensitive hypertension with microarray data and bioinformatics analysis. METHODS: Gene expression data set GSE4800 was downloaded from Gene Expression Omnibus database, including 6 gene chips from 3 Dahl salt sensitive (DS) rat samples and 3 Lewis (LEW) rat samples. Raw data were preprocessed and normalized, and then differentially expressed genes (DEGs) were identified with Limma package. Interaction network was constructed by employing STRING (Search Tool for the Retrieval of Interacting Genes) tool. GO (Gene Ontology) enrichment analysis was performed using FuncAssociate tool and pathway analysis was carried out by EASE (Expressing Analysis Systematic Explorer). BLAST (Basic Local Alignment Search Tool) was applied to explore the sequence homology among CYP3A genes in rat and human based on multiple alignments. RESULTS: A total of 1264 DEGs, including 1082 up-regulated genes and 182 down-regulated genes were identified between DS and LEW samples. CYP3A2 and CYP3A9 were selected to construct the protein interaction network, which comprised 1653 pairs of interaction relationship among 100 genes. Functional analysis showed that CYP3A2 and CYP3A9 were most significantly related to oxidation reduction and metabolism of xenobiotics by cytochrome P450. Furthermore, the CYP3A2 and CYP3A9 genes in rats had high homology with genes CYP3A4and CYP3A5 in human beings. CONCLUSIONS: CYP3A4 and CYP3A5 may contribute to salt-sensitive hypertension in human which may act as biomarkers for this disease.

Laparoscopic versus open repair for strangulated groin hernias: 188 cases over 4 years.

INTRODUCTION: Currently transabdominal pre-peritoneal and totally extraperitoneal repairs are the two standard laparoscopic approaches for groin hernia repair. However, they are still largely reserved for uncomplicated elective cases. To determine whether laparoscopic groin hernia repair can achieve similar results for acute strangulated hernias as laparoscopic cholecystectomy for acute cholecystitis, we analyzed and compared the results of emergency laparoscopic surgery and open repair for strangulated groin hernias performed by our team over the past 4 years. METHODS: This is a retrospective analysis of prospectively collected data. We analyzed the results of patients admitted between January 2007 and January 2011 who were diagnosed with acute strangulated groin hernia and underwent emergency open or laparoscopic hernia repair during the same admission. Patients' demographic details, mode of presentation, type of hernia, intraoperative findings, operative time, postoperative course and complications were compared. RESULTS: In total, 188 patients fulfilled the criteria for emergency surgical repair of strangulated groin hernias; 57 received laparoscopic and 131 received open repairs. The mean operative time was 79.82 ± 29.571 min and 80.75 ± 35.161 min, respectively. More laparotomies were performed in the open group (19 vs 0). The wound infection rate was significantly higher in the open group (12 vs 0). The mean hospital stay was shorter in the laparoscopic group (4.39 days vs 7.34 days). There was no mesh infection in either group. Recurrence occurred one case in the laparoscopic group and in three cases in the open group. CONCLUSIONS: Emergency laparoscopic repair for strangulated groin hernias is feasible and appears to have a lower morbidity relative to open repair. Further study should be performed to evaluate its full potential.

Effect of a traditional Chinese medicine Liu Wei Di Huang Wan on the activities of CYP2C19, CYP2D6 and CYP3A4 in healthy volunteers.

Liu Wei Di Huang Wan (LDW), a well-known traditional Chinese medicine, is widely used for the treatment of various diseases in China. This study was designed to investigate the potential herb-drug interactions of LDW in healthy volunteers and attempted to ascertain whether the interaction might be affected by genotypes. We assessed the effect of LDW on the activities of CYP2C19, CYP2D6 and CYP3A4 in 12 Chinese healthy subjects in a single-center, controlled, non-blinded, two-way crossover clinical trial. The subject pool consisted of six extensive metabolizers with CYP2C19*1/*1 and six poor metabolizers with CYP2C19*2/*2. Placebo or 4.8 g LDW (12 pills, 0.2 g/pill, twice daily) was given to each participant for 14 continuous days with a wash-out period of 2 weeks after an oral administration of 30 mg omeprazole, 30 mg dextromethorphan hydrobromide and 7.5 mg midazolam. The activities of CYP2C19, CYP2D6 and CYP3A4 were ascertained by their respective plasma or urinary metabolic ratios on day 14 post-treatment. There is no difference in the activities of the three tested enzymes before or after a 14-day administration of LDW. LDW had no effect on the pharmacokinetic parameters of the substrates and their metabolites. A 14-day administration of LDW did not affect the activities of CYP2C19, CYP2D6 and CYP3A4. LDW is unlikely to cause pharmacokinetic interaction when it is combined with other medications predominantly metabolized by these enzymes.

Single-incision transabdominal preperitoneal and totally extraperitoneal repair for inguinal hernia: early experience from a single center in Asia.

INTRODUCTION: Laparoscopic inguinal hernia repair is currently one of the most commonly performed minimally invasive surgical procedures. In recent years, single-incision operations have been developed to further reduce the invasiveness of the surgery. Herein, we report our early experience with single-incision laparoscopic inguinal hernia repair in Asia, with both the transabdominal preperitoneal (TAPP) and totally extraperitoneal (TEP) approaches. METHODS: This is a retrospective review of prospectively collected data on a cohort of consecutive patients with inguinal hernia who underwent single-incision laparoscopic inguinal hernia repair in a minimal access surgical center in Hong Kong between January 2010 and January 2011. RESULTS: Our cohort consists of 15 patients who underwent single-incision laparoscopic inguinal hernia; 13 were unilateral and two were bilateral hernias. The mean age was 59.8 years old (range, 28-74 years). The overall mean operative time was 59.53 min (range, 25-120 min). For unilateral hernia repair, the mean operative time was 56 min (range, 25-75 min) and 48.5 min (range, 41-55 min) for TAPP and TEP, respectively. In all cases single-incision laparoscopic hernia repair was successfully performed, no additional trocars were required, and there were no conversions to conventional laparoscopic or open inguinal hernia repair. All patients were discharged on the same day as the procedure. CONCLUSION: Single-incision laparoscopic inguinal hernia is feasible in both TEP and TAPP approaches. The procedure should be performed by laparoscopic surgeons with a high level of experience in single-incision surgery. Further randomized trials should be performed to evaluate the full potential and clinical application of single-incision TAPP and TEP.

Immunoglobulin G4-associated sclerosing cholangitis mimicking cholangiocarcinoma.

Immunoglobulin G4-related lymphoplasmacytic sclerosing disease is an emerging disease. Recently, it has been shown to be responsible for autoimmune pancreatitis-induced strictures of the bile duct mimicking cholangiocarcinoma. Making a diagnosis of immunoglobulin G4-associated sclerosing cholangitis requires a high index of suspicion. The differential diagnoses include primary sclerosing cholangitis, cholangiocarcinoma, and pancreatic cancer. The preoperative diagnosis is likely to be missed due to the lack of specific symptoms; a clinical presentation that may mimic other disorders, especially malignant biliary strictures; and the lack of specific imaging features. This article reports on a 51-year-old man with immunoglobulin G4-associated sclerosing cholangitis without autoimmune pancreatitis. He underwent resection of his extrahepatic bile duct with a hepaticojejunostomy. The diagnosis was confirmed after a histopathological examination. This case highlights the obstacles to making a preoperative diagnosis of immunoglobulin G4-associated sclerosing cholangitis.

Laparoscopic exploration of common bile duct in post-gastrectomy patients.

BACKGROUND/AIMS: To evaluate the results of laparoscopic exploration of the common bile duct (LECBD) in patients with previous gastrectomy. METHODOLOGY: This study is a retrospective review of a prospectively maintained database of LECBD during the period 1994-2005. Those cases of LECBD with previous open gastrectomy were sorted out and analyzed. Indications of operation included unsuccessful endoscopic extraction due to altered anatomy and some explorations were performed together with side-to-side choledochoduodenostomy so as to eliminate biliary stasis and decrease stone recurrence. The operation steps involved open insertion of trocar and creation of pneumoperitoneum, meticulous adhesiolysis, direct choledochotomy followed by clearance of biliary stones. After confirmed ductal clearance, the common bile duct was routinely closed with t-tube diversion. The perioperative parameters of these patients were analyzed and compared to those receiving open exploration of common bile duct due to previous gastrectomy during the same study period. RESULTS: Of the 184 LECBD performed between 1994 and 2005, 33 patients had previous open upper gastrointestinal operations and among them 18 LECBD were performed in post-gastrectomy patients (2 with previous classical Whipple's operation). There were 10 male and 8 female patients with mean age of 77.5 (58-97 years). Of the 14 patients undergoing preoperative endoscopic retrograde cholangiopancreatography, there were 10 failed cannulations and 4 failed extractions. Altogether 17 choledochotomies and 1 transcystic duct exploration was performed whereas 4 patients with recurrent primary stones received additional choledochoduodenostomy. Median operating time was 120 min (60-390 min). Open conversion was required in 3 patients (16.6%) because of jammed basket, extensive adhesion and "through & through" bile duct injury respectively. Postoperative complications occurred in 4 patients (22.2%), which included 3 bile leaks and also the previously mentioned bile duct injury. The median hospital stay was 9 days (4-82 days). Upon a median follow-up of 17.5 months, there was only 1 patient found to have recurrent common bile duct stone and he was managed by laparoscopic exploration and choledochoduodenostomy. When the results were compared to those 12 open explorations because of previous open gastrectomy, longer operation time (120 vs. 75 min, p=0.004) and slightly shorter hospital stay (9 vs. 14 days, p=0.104) were noted in the LECBD group but without increased complication rate (22.2 vs. 25%, p=1). CONCLUSIONS: These results suggest that LECBD is worth attempting even in patients with previous open gastrectomy.

A single-centre experience of 40 laparoscopic liver resections.

OBJECTIVE: To review results of laparoscopic liver resections, particularly in those patients with hepatic malignancy and recurrent pyogenic cholangitis. DESIGN: Retrospective analysis. SETTING: Minimal access surgery training centre, Hong Kong. PATIENTS: Patients with pathologies located at anterio-inferio-lateral segments (Couinaud segments 2, 3, 4b, 5, 6) for laparoscopic resection were recruited during the period 1998 to 2005. Patients were excluded from review if they had: pathologies at central locations and the superior and posterior segments (4a, 7, 8), large tumours (>5 cm in diameter), and those close to major vasculature or the liver hilum. RESULTS: During the study period, we attempted 40 such laparoscopic liver resections, excluding marsupialisations and resections for simple liver cysts. There were 20 female and 20 male patients, with a mean age of 57 (standard deviation, 13; range, 29-81) years. All but one underwent a successful laparoscopic operation. Pathology included hepatocellular carcinoma (n=17), recurrent pyogenic cholangitis (n=14), colorectal liver metastasis (n=4), benign liver tumour (n=4), and intrahepatic cholangiocarcinoma (n=1). All except four were hand-assisted laparoscopic liver resections. The mean operating time was 169 (range, 60-290) minutes and mean blood loss amounted to 270 mL (range, 0-1000 mL). Complications occurred in eight (20%) patients, which included six wound infections, one postoperative bile leak, and two incisional hernias. There was no operative or hospital mortality. For hepatocellular carcinoma, clear resection (>10 mm) was achieved in all except five patients, and the 1-year and 2-year survival rates were 86% and 59% respectively. Favourable results were also obtained for resections in patients with recurrent pyogenic cholangitis; after a mean (standard deviation) follow-up of 29 (23) months, only one was readmitted (for cholangitis). CONCLUSION: In appropriately selected patients, laparoscopic liver resection is feasible and safe, and achieves acceptable survival among individuals with hepatic malignancy and very favourable long-term outcomes in those with recurrent pyogenic cholangitis undergoing hand-assisted laparoscopic segmentectomy.

Immediate preoperative laparoscopic staging for squamous cell carcinoma of the esophagus.

BACKGROUND: Conventional preoperative staging for esophageal carcinoma could be inaccurate. Laparoscopy has been applied for the staging of various upper gastrointestinal malignancies. It can identify peritoneal and liver deposits not shown by imaging, and could reduce the number of nontherapeutic laparotomies. This study aimed to evaluate the efficacy of laparoscopic staging for the management of squamous cell carcinoma involving the mid and distal esophagus. METHODS: A retrospective review was performed for all patients with esophageal cancer evaluated for surgical resection from January 1998 to January 2004. Laparoscopy was performed for all the patients with mid and distal esophageal cancer immediately before open gastric mobilization. The efficacy of laparoscopy for the management of squamous cell carcinoma of the esophagus was evaluated. RESULTS: Among the 63 patients with potentially resectable disease shown on conventional imaging, 54 (84%) underwent esophagectomy with curative intent after laparoscopic staging. Seven patients (11%) underwent laparoscopy alone because of abdominal metastases (n = 5) or other medical conditions (n = 2) that precluded esophagectomy. Two patients (3%) had exploratory right thoracotomy without esophagectomy despite normal laparoscopic findings. The sensitivity and specificity of laparoscopic staging were 100% in this series of patients (100% sensitivity and specificity means no false-positives or -negatives). CONCLUSION: Laparoscopic staging is valuable for the management of patients with mid and distal squamous cell carcinoma of the esophagus. Patients with metastatic disease and those with prohibitive surgical risk can thus avoid unnecessary laparotomy and be offered other treatment methods.

Acute gastric volvulus: an unusual cause of gastric outlet obstruction.

Gastric outlet obstruction initiated by acute gastric volvulus is rare but potentially fatal. An unusual case of intrathoracic acute gastric volvulus complicated by distal stomach and transverse colon herniation into retrocardial space is reported. Prompt clinical diagnosis was followed by emergency laparoscopic de-rotation and gastropexy.

A spike in parathyroid hormone during neck exploration may cause a false-negative intraoperative assay result.

HYPOTHESIS: We hypothesize that false-negative results using the rapid intraoperative parathyroid hormone (IOPTH) assay can be caused by spikes in the level of parathyroid hormone that occur during mobilization of the adenoma. DESIGN: Retrospective analysis of a case series. SETTING: University tertiary care center. PATIENTS: Ten consecutive patients with primary hyperparathyroidism. INTERVENTIONS: All patients underwent neck exploration with IOPTH monitoring. Using a sampling protocol described in the literature, IOPTH values were checked at the time of incision, during mobilization of the adenoma, and 10 minutes after resection of the adenoma. MAIN OUTCOME MEASURES: Patients were evaluated for adequate parathyroid tissue excision as determined by IOPTH levels and examination of ipsilateral glands. All patients had normal serum calcium values documented postoperatively. Parathyroid hormone half-life was calculated assuming first-order kinetic decay. RESULTS: Nine patients had an appropriate decline in IOPTH with a mean +/- SD parathyroid hormone half-life of 3.9 +/- 1.08 minutes. Mobilization of the adenoma resulted in a spike in the IOPTH value, with 1 patient's value increasing from a baseline of 95.5 pg/mL (10.1 pmol/L) to 751 pg/mL (79.1 pmol/L). Another patient who was confirmed to have a solitary adenoma had a false-negative postexcision value. A spike in IOPTH that occurred during neck dissection was not detected by the sampling protocol and explains the false-negative value. A literature review revealed that most protocols check baseline values early in the operation and are at risk for false-negative results due to a spike from mobilization of the adenoma. CONCLUSIONS: These data demonstrate that false-negative IOPTH assay findings can result from a spike in parathyroid hormone level during exploration, which may go unrecognized if baseline values are measured during the early stages of mobilization of the adenoma. We have altered our assay protocol and have begun measuring IOPTH at the time of neck incision, at the time the adenoma is completely removed (time zero [t(0)]), and 10 minutes after excision.

Unusual methyl-branched alpha,beta-unsaturated acyl chain substitutions in the Nod Factors of an arctic rhizobium, Mesorhizobium sp. strain N33 (Oxytropis arctobia).

Mesorhizobium sp. strain N33 (Oxytropis arctobia), a rhizobial strain isolated in arctic Canada, is able to fix nitrogen at very low temperatures in association with a few arctic legume species belonging to the genera Astragalus, Onobrychis, and Oxytropis. Using mass spectrometry and nuclear magnetic resonance spectroscopy, we have determined the structure of N33 Nod factors, which are major determinants of nodulation. They are pentameric lipochito-oligosaccharides 6-O sulfated at the reducing end and exhibit other original substitutions: 6-O acetylation of the glucosamine residue next to the nonreducing terminal glucosamine and N acylation of the nonreducing terminal glucosamine by methyl-branched acyl chains of the iso series, some of which are alpha,beta unsaturated. These unusual substitutions may contribute to the peculiar host range of N33. Analysis of N33 whole-cell fatty acids indicated that synthesis of the methyl-branched fatty acids depended on the induction of bacteria by plant flavonoids, suggesting a specific role for these fatty acids in the signaling process between the plant and the bacteria. Synthesis of the methyl-branched alpha,beta-unsaturated fatty acids required a functional nodE gene.

Genomic structure of the promoters of the human estrogen receptor-alpha gene demonstrate changes in chromatin structure induced by AP2gamma.

Expression of human estrogen receptor-alpha (ERalpha) involves the activity from several promoters that give rise to alternate untranslated 5' exons. However, the genomic locations of the alternate 5' exons have not been reported previously. We have developed a contig map of the human ERalpha gene that includes all of the known alternate 5' exons. By using S1 nuclease and 5'- rapid amplification of cDNA ends, the cap sites for the alternate ERalpha transcripts E and H were identified. DNase I-hypersensitive sites specific to ERalpha-positive cells were associated with each of the cap sites. A DNase I-hypersensitive site, HS1, was localized to binding sites for AP2 in the untranslated region of exon 1 and was invariably present in the chromatin structure of ERalpha-positive cells. Overexpression of AP2gamma in human mammary epithelial cells generated the HS1-hypersensitive site. The ERalpha promoter was induced by AP2gamma in mammary epithelial cells, and trans-activation was dependent upon the region of the promoter containing the HS1 site. These results demonstrate that AP2gamma trans-activates the ERalpha gene in hormone-responsive tumors by inducing changes in the chromatin structure of the ERalpha promoter. These data are further evidence for a critical role for AP2 in the oncogenesis of hormone-responsive breast cancers.

Distal emboli as an unusual late complication of a thrombosed arteriovenous hemodialysis graft.

The creation of an arteriovenous fistula for long-term hemodialysis access is one of the most commonly performed procedures in vascular and transplantation surgery. Prosthetic conduits are frequently prone to failure within their first year of construction, and after one or two revisions, they are left in their thrombosed state as permanent subcutaneous foreign bodies in the extremities. Conventional teaching has regarded these chronically thrombosed grafts to have a benign natural history, and their removal has been considered unnecessary. We describe an unusual late complication of distal thromboemboli from a chronically occluded arteriovenous graft that was implanted 10 years before and appeared as acute hand ischemia.

Nitric oxide, an important regulator of perfusion-contraction matching in conscious pigs.

We examined whether nitric oxide (NO) inhibition during moderate reduction in coronary blood flow (CBF) would affect perfusion-contraction matching. Coronary stenosis (CS) was induced in conscious pigs, which resulted in a stable 39 +/- 1% reduction in CBF for 1.5 h. Ischemic zone wall thickening (IZWT) decreased by an average of 56 +/- 2% during CS from 2.7 +/- 0.2 mm. After reperfusion, myocardial stunning was observed, but this recovered without evidence of necrosis. After recovery and subsequent administration of systemic NO synthase inhibition (N(omega)-nitro-L-arginine, 25 mg. kg(-1). day(-1) x 3 days), CS for 1.5 h reduced CBF similarly but decreased IZWT significantly more, P < 0.05, by 89 +/- 5%. Myocardial stunning, i.e., the decrease in IZWT at 12 h post-CS, was more severe (-65 +/- 5% vs. -21 +/- 3%), P < 0.05. Furthermore, CS during NO synthase inhibition resulted in multifocal subendocardial areas of necrosis in the area at risk. These data suggest that in the intact, conscious pig, NO inhibition prevents perfusion-contraction matching, resulting in intensification of post-ischemic stunning and development of subendocardial necrosis.