Non-operative management of small cell carcinoma of esophagus.

Primary small cell carcinoma of the esophagus (SmCC) is an uncommon aggressive tumor characterized by early systemic dissemination and poor prognosis, regardless of the methods of treatment. The optimal treatment strategy remains uncertain. A retrospective study was conducted to review the results of non-operative treatment for patients with limited and metastatic esophageal SmCC. Between 1993 and 2003, 10 patients were diagnosed to have primary esophageal SmCC in our institution. Six of them had disseminated diseases, whereas the other four had limited disease upon diagnosis. All patients were managed non-operatively by either chemotherapy and/or radiotherapy. The overall median survival was 8 months (range, 2-62 months). The survival was 4-62 months for patients with limited disease, whereas it was 2-10 months for patients with disseminated disease at initial diagnosis. In summary, the current study demonstrated satisfactory palliation could be achieved with chemo-radiation for patients with limited disease; however, the ultimate role of primary chemo-radiation for esophageal SmCC must await results from randomized trials.

Use of mouse models to evaluate roles of nuclear receptors and their ligands in the pathogenesis and treatment of atherosclerosis.

Nuclear receptors form a large family of ligand-dependent transcription factors that regulate diverse aspects of development and homeostasis. Several of these receptors have been demonstrated to play important roles in controlling biological processes that influence the development and clinical consequences of atherosclerosis. Because nuclear receptors are regulated by small molecules, they are potential targets for anti-atherogenic drugs. In this chapter, we review the use of mouse models to evaluate roles of nuclear receptors and their ligands in the pathogenesis and treatment of atherosclerosis.

Immunolocalization of duodenal cytochrome B: a relationship with circulating markers of iron status.

BACKGROUND: The brush border ferric reductase (Dcytb) is critical for the absorption of dietary iron and appears to be expressed on the duodenal enterocyte brush border. The Dcytb expression is increased in severe iron-deficient anaemia, but the situation in a more typical mild iron deficiency is unclear. This study investigated Dcytb expression in patients with normal iron status or mild iron deficiency and its relationships with enterocyte iron status. MATERIALS AND METHODS: Duodenal biopsy specimens and blood samples were obtained from 32 patients undergoing routine upper gastrointestinal endoscopy. Twenty-three specimens (six iron-deficient and 17 iron-replete) were processed for light-microscopy (LM) and for immunohistochemistry with antibodies against Dcytb and heavy/light chain ferritin subunits. The nine remaining biopsies (three iron-deficient and six iron-replete) were processed for electron microscopy (EM). Immunolocalization of Dcytb and intracellular ferritin was performed with appropriate primary antibodies followed by 10-nm gold conjugate labels. RESULTS: The LM process showed a strong negative correlation between immunolabelling intensity of Dcytb on the enterocyte brush border and serum iron saturation (P < 0.001), but only a weak negative correlation between this antigen and haemoglobin (P = 0.08) or serum ferritin concentrations (P = 0.4). EM confirmed anti-Dcytb preferential labelling of microvilli rather than enterocyte cytoplasm (P = 0.001), but preferential antiferritin labelling of cytoplasm (P < 0.02). There was no correlation with enterocyte cytoplasmic ferritin labelling (i.e. enterocyte iron status and Dcytb expression). CONCLUSIONS: Enterocyte Dcytb brush border expression is increased even in mild iron deficiency and may be related to serum iron saturation. The lack of correlation with enterocyte ferritin expression deserves further study with direct measurement of intracellular iron.

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.

Percutaneous cholecystostomy for the treatment of acute cholecystitis in the critically ill and elderly.

OBJECTIVE: To evaluate the clinical efficacy and outcomes of percutaneous cholecystostomy as an alternative treatment option for elderly and critically ill patients who have acute cholecystitis. PATIENTS AND METHODS: The medical records of patients who underwent emergency percutaneous cholecystostomy at the North District Hospital, Hong Kong from September 1999 to July 2002 were reviewed. Indications for the procedure, patient demographics, and other clinical details were recorded. RESULTS: A total of 25 patients (10 male, 15 female) with a median age of 81 years (range, 39-97 years) presented with acute cholecystitis and underwent percutaneous cholecystostomy with ultrasound guidance. Two patients required emergency cholecystectomy on day 1 after the procedures because of deteriorating conditions. The rest of the patients clinically improved after drainage. There was no major periprocedural complication, and four patients had their catheter accidentally dislodged but did not require re-insertion. There were five in-patient mortalities, although the majority of these deaths were from unrelated illness. Subsequently, only six patients underwent elective cholecystectomy, one open and five laparoscopic. Two patients were offered percutaneous endoscopic cholecystolithotripsy, one defaulted and the other could not tolerate the procedure. Eleven patients declined further intervention due to the high surgical risks, three of these patients developed biliary symptoms, one had acute cholecystitis, and the other two had cholangitis. The rest of patients had no symptoms related to the gallstones. The median follow-up period was 81 weeks (range, 27-162 weeks). CONCLUSION: Percutaneous cholecystostomy is a viable treatment option for elderly and critically ill patients presenting with acute cholecystitis. It has a high success rate with minimal procedure-related complications. Elective cholecystostomy is the treatment of choice for low-risk patients after the initial acute cholecystitis.

The safety, feasibility, and acceptability of patient-controlled sedation for colonoscopy: prospective study.

OBJECTIVE: To assess the safety, feasibility, and acceptability of patient-controlled sedation for elective day-case colonoscopy, and the factors predicting patients' unwillingness to use patient-controlled sedation for colonoscopy. DESIGN: Prospective, non-randomised study. SETTING: University-affiliated endoscopy centre, Hong Kong. PARTICIPANTS: Five hundred patients who underwent elective day-case colonoscopy were prospectively recruited from January 2001 to June 2002. INTERVENTION: Sedation for colonoscopy was a mixture of propofol and alfentanil, which was delivered by means of a patient-controlled syringe pump. Each bolus delivered 4.8 mg propofol and 12 microg alfentanil. No loading dose was used and the lockout time was set at zero. MAIN OUTCOME MEASURES: Cardiopulmonary complications, dose of patient-controlled sedation used, recovery time, satisfaction score, delayed side-effects, and the willingness to use the same sedation protocol for future colonoscopy. A multiple stepwise logistic regression model was used to assess which factors might predict unwillingness to use patient-controlled sedation for colonoscopy. RESULTS: The mean (standard deviation) age of patients was 53.0 (13.9) years. The mean dose of propofol consumed was 0.93 (0.69) mg/kg. Forty-three (8.6%) patients developed hypotension during the procedure. The mean satisfaction score was 7.2 (2.6). Sixteen (3.2%) patients developed delayed side-effects. The median (interquartile range) recovery time was 0 (0-5) minutes. Approximately 78% of patients were willing to use patient-controlled sedation for future colonoscopy if needed. Younger age (<50 years), female sex, a higher mean dose of sedatives used, a lower satisfaction score, and the presence of delayed side-effects were independent factors that were associated with patients' unwillingness to use patient-controlled sedation for colonoscopy. CONCLUSION: . The use of patient-controlled sedation for elective colonoscopy is safe, feasible, and acceptable to most patients.

Can visual distraction decrease the dose of patient-controlled sedation required during colonoscopy? A prospective randomized controlled trial.

BACKGROUND AND STUDY AIMS: We previously demonstrated that audio distraction using relaxation music could lead to a decrease in the dose of sedative medication required and improve patient satisfaction during colonoscopy. This prospective randomized controlled trial was designed to test the hypotheses that visual distraction may also decrease the requirement for sedatives and that audio and visual distraction may have additive beneficial effects when used in combination. PATIENTS AND METHODS: 165 consecutive patients who underwent elective colonoscopy were randomly allocated into three groups to receive different modes of sedation: group 1 received visual distraction and patient-controlled sedation (PCS); group 2 received audiovisual distraction and PCS; group 3 received PCS alone. A mixture of propofol and alfentanil, delivered by a Graseby 3300 PCA pump, was used for PCS in these groups. Each bolus of PCS delivered 4.8 mg propofol and 12 micro g alfentanil. Measured outcomes included the dose of PCS used, complications, recovery time, pain score, satisfaction score, and willingness to use the same mode of sedation if the procedure were to be repeated. RESULTS: Eight patients were excluded after randomization. The mean+/-SD dose of propofol used in group 2 (0.81 mg/kg +/- 0.49) was significantly less than the dose used in group 1 (1.17 mg/kg +/- 0.81) and that used in group 3 (1.18 mg/kg +/- 0.60) ( P < 0.01, one-way analysis of variance). The mean +/- SD pain score was also lower in group 2 (5.1 +/- 2.5), compared with the pain scores in group 1 (6.2 +/- 2.2) and group 3 (7.0 +/- 2.4) ( P < 0.01, one-way analysis of variance). The mean +/- SD satisfaction score was higher in groups 1 (8.2 +/- 2.4)) and 2 (8.4 +/- 2.4), compared with the score in group 3 (6.1 +/- 2.9) ( P < 0.01, one-way analysis of variance). A majority of patients in groups 1 (73 %) and 2 (85 %) said that they would be willing to use the same mode of sedation again, compared with only 53 % in group 3 ( P < 0.01, chi-squared test). CONCLUSIONS: Visual distraction alone did not decrease the dose of sedative medication required for colonoscopy. When audio distraction was added, both the dose of sedative medication required and the pain score decreased significantly. Both visual and audiovisual distraction might improve patients' acceptance of colonoscopy.

Outpatient laparoscopic cholecystectomy in Hong Kong: patient acceptance.

The authors performed a prospective evaluation of 60 Hong Kong Chinese patients with symptomatic gallstones and gallbladder polyps undergoing outpatient laparoscopic cholecystectomy in a regional hospital in Hong Kong from March 1996 to May 1998 to determine the feasibility, satisfaction, and acceptance of this procedure among Chinese patients. Patients with American Society of Anesthesiologists grade I and II gallstones or polyps were selected. Exclusion criteria included 1) history of upper abdominal operations, attacks of acute cholecystitis, cholangitis, or pancreatitis; 2) abnormal liver function; and 3) ultrasonographic evidence of contracted gallbladder, thickened gallbladder wall, dilated common bile duct, or common bile duct stones. Patients discharged at 5:00 PM on the day of cholecystectomy were defined as having undergone outpatient procedure. Patients were asked about procedure acceptance, rated on a scale of 1 to 10 (best), using a standardized questionnaire 4 weeks after operation. The study included 21 men and 39 women with mean age of 40.5 years (range, 27-59). There were no conversions to open procedures in the series. There were 6 (10%) unanticipated postoperative hospital admissions; all patients were discharged on the first postoperative day. Another patient was readmitted 3 days after operation because of a common bile duct stone. Overall patient acceptance of outpatient laparoscopic cholecystectomy was good, with a mean score of 8.6 of 10. Thirteen patients (22%) expressed dissatisfaction with being discharged earlier than they had expected, and 9 (15%) would have preferred inpatient care. Forty-eight patients (80%) resumed full daily activities by the first postoperative day; the remaining 12 did so by the end of the first week. Among the 44 working patients, only 4 (9%) resumed full duty within the first postoperative week; 29 (66%) did so by the second week and the remaining 11 (25%) returned to work after the third week. By selecting appropriate subjects, outpatient laparoscopic cholecystectomy is feasible and highly accepted among Hong Kong Chinese patients. Approximately one quarter of the patients preferred a longer postoperative stay or inpatient care.

Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice.

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that regulates fat-cell development and glucose homeostasis and is the molecular target of a class of insulin-sensitizing agents used for the management of type 2 diabetes mellitus. PPARgamma is highly expressed in macrophage foam cells of atherosclerotic lesions and has been demonstrated in cultured macrophages to both positively and negatively regulate genes implicated in the development of atherosclerosis. We report here that the PPARgamma-specific agonists rosiglitazone and GW7845 strongly inhibited the development of atherosclerosis in LDL receptor-deficient male mice, despite increased expression of the CD36 scavenger receptor in the arterial wall. The antiatherogenic effect in male mice was correlated with improved insulin sensitivity and decreased tissue expression of TNF-alpha and gelatinase B, indicating both systemic and local actions of PPARgamma. These findings suggest that PPARgamma agonists may exert antiatherogenic effects in diabetic patients and provide impetus for efforts to develop PPARgamma ligands that separate proatherogenic activities from antidiabetic and antiatherogenic activities.

Protective immune responses against protease-like antigens of the murine malaria parasite Plasmodium vinckei.

The Plasmodium falciparum proteins serine repeat antigen (SERA) and serine repeat protein homologue (SERPH) have similarity in sequence with cysteine proteases in a well-conserved protease domain. We identified three SERA homologues from the murine malaria parasite Plasmodium vinckei and evaluated immune responses to the protease domains of these proteins. Mice that developed protective immunity to P. vinckei after serial infection and cure demonstrated humoral and cell-mediated responses against the SERA homologue protease domains. Mice immunized with Salmonella typhimurium expressing the protease domain of one of these antigens demonstrated cellular responses against the antigen and increased survival against lethal challenge with P. vinckei. Our results suggest that the protease domains of SERA and SERPH are worthy of additional study as potential components of a malaria vaccine.

Differential utilization of Ras signaling pathways by macrophage colony-stimulating factor (CSF) and granulocyte-macrophage CSF receptors during macrophage differentiation.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) independently stimulate the proliferation and differentiation of macrophages from bone marrow progenitor cells. Although the GM-CSF and M-CSF receptors are unrelated, both couple to Ras-dependent signal transduction pathways, suggesting that these pathways might account for common actions of GM-CSF and M-CSF on the expression of macrophage-specific genes. To test this hypothesis, we have investigated the mechanisms by which GM-CSF and M-CSF regulate the expression of the macrophage scavenger receptor A (SR-A) gene. We demonstrate that induction of the SR-A gene by M-CSF is dependent on AP-1 and cooperating Ets domain transcription factors that bind to sites in an M-CSF-dependent enhancer located 4.1 to 4.5 kb upstream of the transcriptional start site. In contrast, regulation by GM-CSF requires a separate enhancer located 4.5 to 4.8 kb upstream of the transcriptional start site that confers both immediate-early and sustained transcriptional responses. Results of a combination of DNA binding experiments and functional assays suggest that immediate transcriptional responses are mediated by DNA binding proteins that are constitutively bound to the GM-CSF enhancer and are activated by Ras. At 12 to 24 h after GM-CSF treatment, the GM-CSF enhancer becomes further occupied by additional DNA binding proteins that may contribute to sustained transcriptional responses. In concert, these studies indicate that GM-CSF and M-CSF differentially utilize Ras-dependent signal transduction pathways to regulate scavenger receptor gene expression, consistent with the distinct functional properties of M-CSF- and GM-CSF-derived macrophages.

The macrosialin promoter directs high levels of transcriptional activity in macrophages dependent on combinatorial interactions between PU.1 and c-Jun.

Macrosialin is a transmembrane glycoprotein that is highly expressed in macrophages. In the present studies, macrosialin mRNA levels are shown to be markedly up-regulated during macrophage differentiation of bone marrow progenitor cells in response to macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. To investigate the mechanisms responsible for regulation of macrosialin expression, we have isolated the macrosialin gene and performed an initial analysis of its transcriptional regulatory elements. The macrosialin promoter and 7.0 kilobase pairs of 5'-flanking information direct high levels of reporter gene activity in monocyte/macrophage-like cells, but little or no expression in nonmyeloid cells. This pattern of expression is dependent on regulatory elements located between -7.0 and -2.5 kilobase pairs from the transcriptional start site that exhibit strong enhancer activity in macrophages and repressor activity in nonmyeloid cells. Analysis of the proximal macrosialin promoter indicates that combinatorial interactions between at least four classes of transcriptional activators, including PU.1/Spi-1 and members of the AP-1 family are required for basal promoter function. PU.1/Spi-1 and c-Jun act synergistically to activate the macrosialin promoter in a nonmyeloid cell line, suggesting that combinatorial interactions between these proteins are involved in regulating macrosialin expression during macrophage differentiation.

The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation.

The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors that is predominantly expressed in adipose tissue, adrenal gland and spleen. PPAR-gamma has been demonstrated to regulate adipocyte differentiation and glucose homeostasis in response to several structurally distinct compounds, including thiazolidinediones and fibrates. Naturally occurring compounds such as fatty acids and the prostaglandin D2 metabolite 15-deoxy-delta prostaglandin J2 (15d-PGJ2) bind to PPAR-gamma and stimulate transcription of target genes. Prostaglandin D2 metabolites have not yet been identified in adipose tissue, but are major products of arachidonic-acid metabolism in macrophages, raising the possibility that they might serve as endogenous PPAR-gamma ligands in this cell type. Here we show that PPAR-gamma is markedly upregulated in activated macrophages and inhibits the expression of the inducible nitric oxide synthase, gelatinase B and scavenger receptor A genes in response to 15d-PGJ2 and synthetic PPAR-gamma ligands. PPAR-gamma inhibits gene expression in part by antagonizing the activities of the transcription factors AP-1, STAT and NF-kappaB. These observations suggest that PPAR-gamma and locally produced prostaglandin D2 metabolites are involved in the regulation of inflammatory responses, and raise the possibility that synthetic PPAR-gamma ligands may be of therapeutic value in human diseases such as atherosclerosis and rheumatoid arthritis in which activated macrophages exert pathogenic effects.

Speech perception of temporally reversed syllables by normally hearing adults.

BACKGROUND: The general purpose of this study was to determine the effects of phonological knowledge on performance on a simple task of speech discrimination. If a test can be devised that is independent of the subject's phonological knowledge then it should be possible to measure auditory speech perception capacity in young deaf children before they have developed spoken language skills. In the present study, temporal reversal was used to limit normal subjects' use of phonological knowledge without removing acoustic information. METHODS: An auditory, 3-interval, forced-choice (oddity) test of phonetic contrast perception was administered to 5 normally hearing adult speakers of English. Perception of place of articulation was measured in stops and fricatives--both voiced and unvoiced. The test was presented both with natural syllables and with the same syllables reversed in time. In addition, the test was administered with a fixed context and a mixed context (i.e., context changing from trial to trial). The subject's task was always to identify the odd-man-out in each presentation of 3 syllables. RESULTS: Overall, error rate was significantly higher for temporally-reversed than for natural syllables (6.7% versus 1.7%). The effect was, however, present only in stops (11.7% versus 1.7%) and not in fricatives (0.8% versus 0.8%). Changing from a fixed to a mixed context did not influence the effect of reversal. There were, however, significant differences among subjects in the temporally-reversed condition. CONCLUSIONS: The main effect of reversal supports the hypothesis that performance falls, even on a simple task, when phonetic processing is impeded. The fact that the effect is present only for stops adds further support, because temporal reversal does not affect the essential acoustic properties of fricatives. The presence of inter-subject differences suggests that the ability to switch to an acoustic strategy when phonetic processing is impeded may be affected by aptitude and experience. The fact that error rate was low, even for reversed stops, suggests that a test of this type could be used for assessing speech perception capacity in deaf children with impaired phonology. The procedure is not, however, completely independent of the effects of phonetic processing.

Apolipoprotein B upstream suppressor site: identification of an element which can decrease apolipoprotein B transcription.

Elevated plasma levels of apolipoprotein B (apoB) may predispose to development of premature coronary atherosclerosis. We have identified the first well localized domain of the apoB gene which can effect negative regulation of its transcription. This region binds trans-activating factors present only in apoB producing cell lines. Mutagenesis of this region causes up-regulation of its transcriptional activity. We have termed this element apoB upstream suppressor site (aBUSS) and its trans-activators the apoB repressor proteins (ARP). aBUSS and ARP may play important roles in the transcriptional modulation of apoB.