A new fluorinated benzodiazepine compound Ro 5-4200 was used for induction in 58 surgical patients to evaluate the possibility of an intravenous anesthetic induction agent (Table 2 and 3). The hypnotic properties as well as respiratory, cardiovascular, muscle relaxant and local effects were observed. 1. Ro 5-4200 in doses of 2mg was slowly injected intravenously to adult patients (body weight ; 54.2+/-10.3 kg) and 1 mg to a child (body weight; 22 kg, 5 yr.) (Table 2). The tim between the start of injection and the loss of consciousness was 110.3"+/-68.6", taken from the beginning of the injection until the patient was asleep and eyelash and corneal reflexes abolished. Sleep did not occur in 2 patients (Table 4). 2. But the time to sleep after the injection varied remarkebly according to the dilution of the drug. When the dose of 2 mg of the drug was injected, undiluted directly to the small vein, the time to sleep was 83.2"+/-31.4" and 69.1"+/-31.4"; in the former case the patients complained of pain along the injected vein and the latter did not. 3. The hypnotic time with the diluted solution of the drug was 144.5" +/-4.6" and 117.3"+/-77.8", in which the former complained of pain during injection, and the latter did not. 4. Blood pressure, pulse rate and respiratory rate were measured immediately prior to induction and again 2 and 5 minutes after induction. A slight but insignificant rise in blood pressure with a mean of 3.4% in systolic and 6.7% in diastolic pressure above control value was observed in 2 minutes after injection. And at 5 minutes there was a significant fall in blood pressure, 11.3% and 4.3% respectively (p<0.05) (Table 5). 5. Pulse rate increased significantly by 12.7 beats (14.2%) a minute in 2 minutes after injection and 15.7 beat (17.5%) a minute in 5 minutes after injection from a control level of 89.6 (p<0.01) ,(Table 6). 6 Respiration became shallower and the rate decreased as the patients fell asleep. Apnea occurred in 4 patients (6.9%). In the apnea cases, respiration was controlled by mask and positive pressure ventilation. It needed that the facilities for positive pressure ventilation be available in case apnea develops. 7. During induction, tremors, abnormal muscle movements, and laryngospasm were not observed. Hiccough was observed in 4 cases (6.9%). Hiccugh had the tendency to recur during intra-abdominal procedure. 32 patients (55.0%) had an antegrade amnesia, that is shortly before the injection of the drug. They did not remember being moved to the operating table or the insertion of the injection needle. 8. Ro 5-4200 caused pain on injection when given undiluted directly into a small vein on the dorsum of the hand, and the pain was also complained of even when the drug was diluted to 5 times with normal saline or intravenous drip infusion. A localized thrombophlebitis was not seen. 9. Laryngeal reflexes were retained on induction but endotracheal intubation was tried successfully without muscle relaxant in three cases. In this procedure the patients tended to be awake and showed some resistance. The help of muscle relaxants in intubation is recommended. As to degree of everity and nature of muscle fasciculation after succinylcholine, there was somewhat delayed appearance but degree was not altered by Ro 5-4200 10. Recovery from anesthesia and reversal of muscle relaxation was unaltered. The induction was satisfactory, but slow, and characterized by minimal change in blood pressure, pulse rate and respiration. Because of this delayed induction time and the varied degree of depth of sleep, the agent seemed to be improper as an intravenous induction agent. Acknowledgements: Samples of Ro 5-4200 have been kindly supplied by Hoffmann La Roche, Hong Kong. The authors wish to thank Dr. S.S.Lo and Dr. P.A. Bulhr of Roche Products Ltd., for their assistance and advice.
Adult ; Amnesia ; Anesthesia ; Apnea ; Benzodiazepines* ; Blinking ; Blood Pressure ; Child ; Fasciculation ; Flunitrazepam* ; Hand ; Heart Rate ; Hiccup ; Hong Kong ; Humans ; Infusions, Intravenous ; Intubation ; Intubation, Intratracheal ; Laryngismus ; Masks ; Muscle Relaxation ; Needles ; Operating Tables ; Positive-Pressure Respiration ; Reflex ; Respiration ; Respiratory Rate ; Succinylcholine ; Thrombophlebitis ; Tremor ; Unconsciousness ; Veins

Although bladder transitional cell carcinoma (TCC) is common, the underlying molecular events remain ill-defined. So we attempted to define the role of tumor suppressor genes in the pathogenesis of bladder tumor through a molecular genetic study. For 15 bladder TCC (6 gradeII, 1 gradeIII, and 8 grade IV), we performed the restriction fragment length polymorphism (RFLP) analysis for 6 loci of suspected or established tumor suppressor regions (3p21, 3p24-25, llp15, 13q14, and 17p13). Our data confirm that allelic losses are highly common in bladder tumors. We found that alleles from each of the four chromosomal arms tested were lost in most of the tumors. Reduction of allele occured at 3p21 (13%), 3p24~25 (50%), and 13q14 (38%). However, the greatest frequency of allelic loss was seen for 17p 13 (100% of informative cases) and llp15.5 (87% informative cases). Severe allelic losses of chromosome 17p and pADJ762 on lip were seen only in grade IV, not in grade II. Amplification of 3p21 was seen six out of eight. Amplification of 3p21 has not been previously observed on the other study. Addition to this, we observe the loss of H-ras allele on 11p in one case which was associated with duplication of the retained allele as was demonstrated in Wilms'tumors. The results of out study suggest that deletions of pADJ762 on chromosome 11p and 17p13 occur in high grade bladder tumor and may contribute to the progression of this disease. But, there was no apparent correlation between tumor grade and the loss of 3p or 13q14 alleles although they had some deletions. The role of these genetic alterations in the prognosis of bladder transitional cell carcinoma will require additional follow-up and further studies.
Alleles ; Arm* ; Carcinoma, Transitional Cell ; Chromosomes, Human, Pair 11* ; Genes, Tumor Suppressor ; Lip ; Loss of Heterozygosity ; Molecular Biology* ; Polymorphism, Restriction Fragment Length ; Prognosis ; Urinary Bladder Neoplasms* ; Urinary Bladder*

The objective of this study was to characterise the pattern of p53 mutations in bladder tumor. In this study, 25 bladder transitional cell carcinomas were analyzed by immunohisochemistry (IHC) for p53 nuclear overexpression, and the results were compared with those of polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis in exon 5-8 of the p53 gene and DNA sequencing analysis. 15 out of 20 cases (75%) showed p53 nuclear immunoreactivities on IHC. On PCR-SSCP analysis, 10 out of 25 cases (40%) had abnormal shifts in mobility. 62% of the mutations were in exon 8. Direct DNA sequencing analysis were performed in these 10 cases to confirm the presence of mutated p53 genes and to determine the type of mutations. Sixteen point mutations were detected in 10 cases. Two specimens had double mutations and another two had triple mutations. G:C-->A:T transitions were the most frequent patterns (62.5%). One mutation was a premature stop codon and two were silent mutations. Three out of 10 had a point mutation at codon 285 (GAG/Glu-->AAG/Lys) and two had at codon 280 (AGA/Arg-->AAA/Lys). One of 16 mutations was transition at hot spot codon 273 with CpG site. These results suggest that altered expressions and point mutations of p53 occured in all grade of bladder cancer, but are more associated with high grade bladder tumors. To elucidate the carcinogenesis of bladder cancer, further studies should be carried out.
Carcinogenesis ; Carcinoma, Transitional Cell* ; Codon ; Codon, Nonsense ; Exons ; Genes, p53 ; Humans* ; Point Mutation* ; Sequence Analysis, DNA ; Urinary Bladder Neoplasms ; Urinary Bladder*

BACKGROUND: Abnormalities of genomic methylation patterns have been shown to play a role in the development of carcinoma, and the silencing of tumor suppressor genes is related to local de novo methylation. METHODS: Using methylation specific arbitrarily primed-Polymerase Chain Reaction (Ms AP-PCR), we identified a 322 bp sequence that contained a 5' un-translated and exon1 regions of the TPEF gene. To evaluate the inactivation of the TPEF gene through hypermethylation in hepatocellular carcinoma (HCC), we investigated the correlation between methylation patterns and TPEF expression in tumor tissues of human HCC and cell lines via a Combined Bisulfite Restriction Assay (CoBRA) and RT-PCR. RESULTS: A dense methylation pattern of the TPEF was detected in most cell lines, as well as in 10 of the 14 (71.4%) HCC tissues. In addition, loss of heterozygosity (LOH) from the TPEF gene was observed in 5 of the 14 (36%) HCC tissues. Furthermore, RT-PCR analysis revealed TPEF expression in 5 of 8 (62.5%) cell lines. Finally, treatment with a demethylating agent, 5-Aza- 2'-deoxycitidine (5-AzaC), increased the expression of TPEF mRNA. CONCLUSION: These results indicate that inactivation of the TPEF gene through hypermethylation may be a mechanism by which tumorigenesis occurs in HCC.
Humans ; Carcinoma, Hepatocellular ; Cell Transformation, Neoplastic ; Genes, Tumor Suppressor

Germ-line mutations at DNA repair loci confer susceptibility to colon cancer in hereditary non-polypopsis colorectal cancer. Somatic loss of DNA mismatch repair gene has been reported in a large variety of other tumor types. Replication errors(RERs) judged by microsatellite instability(MSI) and its associated mutations have been recognized as an important mechanism in various tumor types. To investigate associations between MSI and oral squamous cell carcinoma, the frequency of MSI using 12 microsatellite markers were analyzed for the series of oral tumors. Of 17 tumors, 8 cases(47%) did not show instability at any of the 12 loci; 5(29%) showed instability at 2~3 loci; and 4(24%) showed instability above 4 loci. The 4 cases showing widespread MSI did not differ from those without evidence of instability in terms of age at diagnosis, degree of differentiation, metastasis to lymph node, tumor location or the presence of mutations in the p53 tumor suppressor gene. DCC and D17S 796 were the most frequently detected in MSI analysis. There were no correlation between smoking and MSI frequency, instead, smoking was suggested to increase the mutation rate of p53 and development of oral carcinomas.
Carcinoma, Squamous Cell* ; Colonic Neoplasms ; Colorectal Neoplasms ; Diagnosis ; DNA Mismatch Repair ; DNA Repair ; Genes, p53* ; Genes, Tumor Suppressor ; Germ-Line Mutation ; Lymph Nodes ; Microsatellite Instability* ; Microsatellite Repeats* ; Mutation Rate ; Neoplasm Metastasis ; Smoke ; Smoking

No abstract available.
Erythrocytes*

Hypermethylation of CpG island is a common mechanism for the inactivation of tumor-related genes. In the present study, we analyzed 13 genitourinary cancer cell lines for aberrant DNA methylation of 5 tumor-related genes using methylation- specific polymerase chain reaction (MSP). GSTP1 was methylated in 5 (38.5%), E-cadherin in 1 (8%), VHL in 1 (8%), and MGMT and hMLH1 in none (0%). Six out of thirteen genitourinary cancer cell lines had methylation of at least one of five genes; 5 had one gene methylated, and, 1 had two genes methylated. Methylation of these 5 genes was not detected in any of the bladder cancer cell lines. GSTP1 was methylated in all of the 3 prostate cancer cell lines. We conclude that aberrant hypermethylation may be an important mechanism for the inactivation of cancer-related genes in kidney and prostate cancer cell lines.
Bladder Neoplasms/genetics ; Cadherins/genetics ; *DNA Methylation ; DNA Primers ; Genetic Screening/methods ; Glutathione Transferase/genetics ; Human ; Isoenzymes/genetics ; Kidney Neoplasms/genetics ; Ligases/genetics ; Male ; Neoplasm Proteins/genetics ; O(6)-Methylguanine-DNA Methyltransferase/genetics ; Polymerase Chain Reaction ; Prostatic Neoplasms/genetics ; Tumor Cells, Cultured ; Urogenital Neoplasms/*genetics

No abstract available.
Erythrocytes*

PURPOSE: This report introduces a new method for tensioning the remnant PCL with a reconstruction of the anterolateral (AL) bundle of the PCL using a modified tibial inlay technique with an assessment of the outcome of this method in chronic PCL injury. MATERIALS AND METHODS: From January 1998 to August 2003, eighty six patients was underwent tensioning of a laxed remnant PCL with a reconstruction of the anterolateral bundle of the PCL. Of these, fifty two patients who were followed up for more than 2 years were evaluated. Tensioning was performed using a distal transfer of the tibial attachment with the posteromedial approach in the supine position. The AL bundle of the PCL was reconstructed with 4 bundles of a hamstring autograft or tibialis anterior tendon allograft. The stability was assessed objectively using stress radiographs with the Telos(R) device and the maximal manual test with the KT-1000 arthrometer. The clinical results were assessed by the IKDC (International Knee Documentation Committee) and OAK (Orthopadische Arbeitsgruppe Knie) scores. The posterior drawer test, varus stress test, posterolateral drawer test and dial test in 30 degrees and 90 degrees flexion were performed for a physical examination. RESULTS: The average side to side difference of the posterior tibial translation in stress radiographs with the Telos(R) device decreased from 10.4+/-2.0 mm to 2.2+/-1.0 mm. The average side to side difference in the maximal manual test with the KT-1000 arthrometer also decreased from 8.2+/-1.5 mm to 1.9+/-1.0 mm. The final IKDC score was A in eleven (21.2%), B in thirty-five (67.3%) and C in six (11.5%) patients. The average OAK score improved from 64.3+/-8.9 to 90.8+/-7.2. CONCLUSION: Tensioning of the laxed remnant PCL with a reconstruction of the AL bundle in chronic PCL injuries showed good clinical results and excellent posterior stability.
Allografts ; Autografts ; Exercise Test ; Humans ; Inlays ; Knee ; Physical Examination ; Posterior Cruciate Ligament* ; Supine Position ; Tendons

PURPOSE: Irinotecan, in combination with leucovorin/ 5-fluorouracil (FU) or with cisplatin, is known to be active for treating advanced gastric cancer (AGC). This pilot study evaluated a novel three-drug combination of irinotecan, leucovorin/FU and cisplatin as a first-line treatment of AGC. The primary endpoint was to assess the feasibility in anticipation of conducting a larger phase II study. MATERIALS AND METHODS: Chemotherapy-naive AGC patients received irinotecan 150 mg/m2 on day 1, and leucovorin 200 mg/m2 and a 22-h infusion of FU 1000 mg/m2 on days 1 and 2. Cisplatin 30 mg/m2 was administered on day 2. Treatment was repeated every 2 weeks until disease progression or unacceptable toxicity. RESULTS: Of the 17 eligible patients, two patients had an ECOG performance status of 2 and their median age was 48 years (range: 31 to 69). A total of 117 chemotherapy cycles were delivered (median: 6, range: 1 to 12). The causes of treatment discontinuation were disease progression in 9 patients (53%), refusal (35%) and toxicity (12%). Although grade 3 or 4 neutropenia (41% of patients) was the major toxicity that required dose adjustments, only one episode of febrile neutropenia occurred. Grade 3 or 4 nausea and vomiting, diarrhea and fatigue were observed in 35%, 35% and 29% of patients, respectively. None of the patients died of toxicity during treatment. Of the 16 patients who were evaluable for response, 7 (44%) experienced a partial response. CONCLUSION: This novel multi-drug combination was tolerated well in patients with AGC. Based on the encouraging efficacy and tolerability, a randomized phase II study is ongoing in this disease setting.
Cisplatin* ; Diarrhea ; Disease Progression ; Disulfiram ; Drug Therapy ; Drug Therapy, Combination* ; Fatigue ; Febrile Neutropenia ; Fluorouracil* ; Humans ; Leucovorin* ; Nausea ; Neutropenia ; Pilot Projects* ; Stomach Neoplasms* ; Vomiting