Randomised phase II study of S-1/cisplatin plus TSU-68 vs S-1/cisplatin in patients with advanced gastric cancer.

BACKGROUND: This study aimed to determine whether combination S-1 plus cisplatin (CDDP) therapy, the most widely used therapy for Japanese patients with advanced gastric cancer, and the novel oral antiangiogenic agent TSU-68 could contribute to gastric cancer treatment. METHODS: Ninety-three patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers were randomised into two groups: TSU-68 plus S-1/CDDP (group A) and S-1/CDDP (group B) groups. Both patient groups received identical S-1 and CDDP dosages. TSU-68 was orally administered for 35 consecutive days. Group B patients received S-1 orally twice daily for three consecutive weeks, followed by intravenous CDDP on day 8. The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS periods were 208 and 213 days in groups A and B, respectively (P=0.427). Median survival periods for groups A and B were 497.0 and 463.5 days, respectively (P=0.219). No statistically significant differences were noted for PFS, survival or the adverse event (AE) incidence rate. All AEs were expected according to previous reports for TSU-68, TS-1, and CDDP. CONCLUSION: Combination therapy involving TSU-68, S-1, and CDDP was safe and well tolerated in patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers. However, factors related to therapeutic efficacy should be investigated further.

Ribosomal protein S7: a new RNA-binding motif with structural similarities to a DNA architectural factor.

BACKGROUND: The ribosome is a ribonucleoprotein complex which performs the crucial function of protein biosynthesis. Its role is to decode mRNAs within the cell and to synthesize the corresponding proteins. Ribosomal protein S7 is located at the head of the small (30S) subunit of the ribosome and faces into the decoding centre. S7 is one of the primary 16S rRNA-binding proteins responsible for initiating the assembly of the head of the 30S subunit. In addition, S7 has been shown to be the major protein component to cross-link with tRNA molecules bound at both the aminoacyl-tRNA (A) and peptidyl-tRNA (P) sites of the ribosome. The ribosomal protein S7 clearly plays an important role in ribosome function. It was hoped that an atomic-resolution structure of this protein would aid our understanding of ribosomal mechanisms. RESULTS: The structure of ribosomal protein S7 from Bacillus stearothermophilus has been solved at 2.5 A resolution using multiwavelength anomalous diffraction and selenomethionyl-substituted proteins. The molecule consists of a helical hydrophobic core domain and a beta-ribbon arm extending from the hydrophobic core. The helical core domain is composed of a pair of entangled helix-turn-helix motifs; the fold of the core is similar to that of a DNA architectural factor. Highly conserved basic and aromatic residues are clustered on one face of the S7 molecule and create a 16S rRNA contact surface. CONCLUSIONS: The molecular structure of S7, together with the results of previous cross-linking experiments, suggest how this ribosomal protein binds to the 3' major domain of 16S rRNA and mediates the folding of 16S rRNA to create the ribosome decoding centre.

Characterization of the secondary structure of an oligonucleotide corresponding to the autocleavage site of a precursor RNA from bacteriophage T4.

We studied the secondary structure of an RNA fragment (GUUUCGUACAAAC) (R1) having the sequence corresponding to the self-cleavage domain in a precursor RNA molecule from bacteriophage T4 infected Escherichia coli cells (p2Sp1 RNA). We synthesized an oligoribonucleotide (CAAACGUACAAAC) (R3) which contained the sequence (CGUACA) proposed for the p2Sp1 RNA self-cleavage site but did not form the hairpin loop structure. The self-cleavage ability of the single stranded RNA (R3) is significantly lower than that of R1. We have also designed a modified RNA fragment (R2), which contained a noncleavable RNA with 2'-O-methylcytidine or 2-O-methyluridine. R3 did not exhibit cleavage. To further investigate the structural requirements in the cleavage reaction, we synthesized mutant RNAs which contained different bases within consensus sequences and the cleavage sites were tested for self-cleavage. Guanosine and adenosine 3'-phosphates seemed not to be susceptible to transesterification at the cleavage site. The data from native gel electrophoresis, the CD spectra and the Tm suggested that the hairpin structure is necessary for the cleavage.

The stem hairpin loop structure of p2Sp1 RNA is required for RNA-cleaving activity.

We studied the hairpin-loop structure of an RNA fragment (GUUUCGUACAAAC) (R13) with the sequence corresponding to the self-cleavage domain in the precursor of an RNA molecule from bacteriophage T4-infected Escherichia coli cells (p2Sp1 RNA). In order to determine the influence of the hairpin-loop structure on these sequence-specific cleavage reactions, we have synthesized oligoribonucleotides containing hairpin-loop, double-helical stem-loop, and single-stranded RNA structures. The cleavage was affected by the hairpin-loop structure. Furthermore, the helix-stem, which retains the thermodynamically extrastable stem hairpin-loop structures, is also important for the cleavage activity. However, the thermodynamically extrastable helix-stem structure reduced the cleavage activity of the adjacent UA and CA sequences at the helix-stem site. For the cleavage reactions of the RNA cleavage products, the R6 (ACAAAC), R7 (GUUUCGU), and R9 (GUUUCGUAC) mers from the parent RNA, R13 (GUUUCGUACAAAC), a very slight amount of cleavage product (2%) from the RNA 9 was observed, but no reaction occurred for the R6 and R7. We also describe the influences of the sequences (UA and CA) on the cleavage activity.

Cleavage effect of oligoribonucleotides substituted at the cleavage sites with modified pyrimidine- and purine-nucleosides.

The precursor of an RNA molecule from T4-infected E. coli cells (p2Spl RNA) has the capacity to cleave itself at specific positions [UpA (139-140) and CpA (170-171)], within a putative loop and stem structure. This sequence-specific cleavage requires at least a monovalent cation and non-ionic detergents. In order to determine the influence of the pyrimidine and purine bases on these sequence-specific cleavage reactions, we studied the cleavage reactions of hairpin loop RNAs substituted at the cleavage sites with modified pyrimidine- and purine-nucleosides. The cleavage was affected by the 2'-hydroxyl groups and the bases of the pyrimidines, and the 6-amino group of the purine.

Variant parameter values-as defined by the Chicago Criteria-produced by ManoScan and a new system with Unisensor catheter.

BACKGROUND: Recently reported normal values for esophageal motility obtained by high-resolution manometry (HRM) using a system with a Unisensor catheter were significantly different from those obtained by the ManoScan(®) , which could result in a wrong diagnosis. To clarify whether these differences were due to system or subject differences, we compared the manometric parameter values between ManoScan and a new system with a Unisensor catheter (Starlet) in the same subjects. METHODS: A total of 103 volunteers without any symptoms related to esophageal motility disorders were recruited. Esophageal HRM was performed using both the ManoScan and the Starlet in all subjects. Data from the ManoScan were analyzed using ManoView, and data from the Starlet were analyzed by a program with e-sleeve function. Integrated relaxation pressure, distal contractile integral, contractile front velocity (CFV), intrabolus pressure, and distal latency were calculated by both analyzing programs, and the values of these parameters were compared between the two systems by a signed rank test. KEY RESULTS: Data from a total of 97 participants were analyzed. The values of all parameters, except CFV, measured by the Starlet were significantly higher than those obtained by the ManoScan (p < 0.01). CONCLUSIONS & INFERENCES: Both systems can measure esophageal motility appropriately; nevertheless, we confirmed that the two systems showed different values of the parameters defined by the Chicago criteria. These differences should be recognized to evaluate esophageal motility precisely.

Cleavage reaction of a synthetic oligoribonucleotide corresponding to the autocleavage site of a precursor RNA from bacteriophage T4.

A fragment (GUUUCGUACAAAC) having a consensus sequence for the self-cleavage domain in a precursor of an RNA molecule from T4-infected Escherichia coli cells (p2Sp1; precursor of species 1) was chemically synthesized and found to be cleaved either between CA (139-140) or between UA (137-138) in the presence of monovalent cations and a non-ionic detergent. The cleaved products had 5'-hydroxyl and 3'-phosphate groups, of which some were in the form 2',3'-cyclic phosphates.

The structure of the archaebacterial ribosomal protein S7 and its possible interaction with 16S rRNA.

Ribosomal protein S7 is one of the ubiquitous components of the small subunit of the ribosome. It is a 16S rRNA-binding protein positioned close to the exit of the tRNA, and it plays a role in initiating assembly of the head of the 30S subunit. Previous structural analyses of eubacterial S7 have shown that it has a stable alpha-helix core and a flexible beta-arm. Unlike these eubacterial proteins, archaebacterial or eukaryotic S7 has an N-terminal extension of approximately 60 residues. The crystal structure of S7 from archaebacterium Pyrococcus horikoshii (PhoS7) has been determined at 2.1 A resolution. The final model of PhoS7 consists of six major alpha-helices, a short 3(10)-helix and two beta-stands. The major part (residues 18-45) of the N-terminal extension of PhoS7 reinforces the alpha-helical core by well-extended hydrophobic interactions, while the other part (residues 46-63) is not visible in the crystal and is possibly fixed only by interacting with 16S rRNA. These differences in the N-terminal extension as well as in the insertion (between alpha1 and alpha2) of the archaebacterial S7 structure from eubacterial S7 are such that they do not necessitate a major change in the structure of the currently available eubacterial 16S rRNA. Some of the inserted chains might pass through gaps formed by helices of the 16S rRNA.

Esophageal PCO2 as a monitor of perfusion failure during hemorrhagic shock.

Measurement of gastric wall PCO2 (PgCO2) by tonometric method has emerged as an attractive option for estimating visceral perfusion during circulatory shock. However, gastric acid secretion obfuscates the tonometric measurement. We, therefore, investigated the option of measuring PCO2 in the esophagus to minimize these restraints. Hemorrhagic shock was induced in five Sprague-Dawley rats, and five rats served as sham controls. PgCO2 was measured with an ion-sensitive field effect transistor that was surgically implanted into the gastric wall. Esophageal luminal PCO2 (PeCO2) was measured by a second ion-sensitive field effect transistor sensor. During hemorrhagic shock, mean aortic pressure declined from 150 to 50 mmHg. Gastric blood flow decreased from 58 to 12 ml.min-1.100 g-1 (21% of preshock) and esophageal blood flow from 44 to 7 ml.min-1.100 g-1 (16% of preshock). PgCO2 simultaneously increased from 47 to 116 Torr and PeCO2 from 47 to 127 Torr. The increases in PgCO2 were highly correlated with increases in PeCO2 (r = 0.90). Esophageal tonometry may, therefore, serve as a practical alternative to gastric tonometry.

Highly active antiretroviral therapy used to treat concurrent hepatitis B and human immunodeficiency virus infections.

We report a case of simultaneous infection with hepatitis B virus (HBV) and human immunodeficiency virus type 1 (HIV-1) in a 26-year-old Japanese homosexual man. He was admitted to our hospital for acute hepatitis caused by HBV. At that time, HIV-1antibody (Ab) was not detected in his serum. After 6 months, he was readmitted to our hospital for further examination of his liver because of confined liver enzyme abnormalities. Anti-HIV- Ab was detected in his serum by both enzyme immunosorbent assay (EIA) and particle agglutination (PA). His serum HIV-1 RNA level was 50 x 10(4) copies/ml and serum levels of HBV DNA polymerase (DNA-P) and HBV DNA were 6535cpm and 3 plus (>1000 copies/ml). His clinical course and laboratory data suggested progression from acute to chronic hepatitis related to coinfection with HIV-1. The diagnosis was chronic active hepatitis caused by HBV as an opportunistic infection due to coinfection with HIV-1. We began highly active antiretroviral therapy (HAART) because interferon (IFN) therapy was ineffective. HAART was started at an initial dosage of 600 mg zidovudine (AZT), 300 mg lamivudine (3TC), and 2400 mg indinavir (IDV) daily. After 4 weeks, the serum level of HBV DNA-polymerase (p) had decreased markedly to 37cpm and that of HIV-1 RNA had decreased to below the sensitivity threshold, indicating considerable suppression of the replication of these viruses by the treatment. But HBV DNA remained at low levels. Although the incidence of HBV infection in patients with HIV-1 infection has been reported to be high in the United States and Europe, simultaneous HBV and HIV-1 infection leading to persistent HBV infection is rare.

Self-cleavage of p2Sp1 RNA with Mg2+ and non-ionic detergent (Brij 58).

The precursor of an RNA molecule from T4-infected E. coli cells (p2Sp1 RNA) has the capacity to cleave itself at specific positions [(UpA (139-140) and CpA (170-171)], within a putative loop and stem structure. This sequence-specific cleavage requires at least a monovalent cation and non-ionic detergents. We studied the self-cleavage reaction of an RNA fragment (GUUUCGUACAAAC) (R1) with the sequence corresponding to the p2Sp1 RNA in the presence of Mg2+ and non-ionic detergents. It requires Mg2+ and is aided by a non-ionic detergent, Brij 58. The cleavage reaction is time, temperature, and pH-dependent. The cleavage occurs at the phosphodiester bond between UpA and CpA on the RNA fragment (GUUUCGUACAAAC) (R1). Furthermore, the maximum of cleavage of R1 occurs at a very low Mg2+ concentration (< or = 5 mM).

Comparative simulation of excitation and body surface electrocardiogram with isotropic and anisotropic computer heart models.

Comparative simulations between isotropic and anisotropic computer heart models were conducted to study the effects of myocardial anisotropy on the excitation process of the heart and on body surface electrocardiogram. The isotropic heart model includes atria, ventricles, and a special conduction system, and is electrophysiologically specified by parameters relative to action potential, conduction velocity, automaticity, and pacing. The anisotropic heart model was created by incorporating rotating fiber directions into the ventricles of the isotropic heart model. The orientation of the myocardial fibers in the ventricles of the model was gradually rotated counterclockwise from the epicardial layer to the endocardial layer for a total rotation of 90 degrees. The anisotropy of conduction velocity and intracellular electric conductivity was included in the simulation. Comparative simulations of the normal heart, LBBB, and RBBB showed no significant differences between the two models in the excitation processes of the whole heart or in the body surface electrocardiograms. However, it was easier to induce ventricular fibrillation in the anisotropic model than in the isotropic model. The comparative simulation is useful for investigating the effects of myocardial anisotropy at the whole heart level and for evaluating limitations of the isotropic heart model.

A comparison of body surface Laplacian and potential maps during paced ventricular activation.

The objective of this study is to evaluate the spatial resolution of body surface Laplacian maps (BSLMs) in localizing ventricular electrical activity by means of computer simulation. A 3-D computer heart-torso model was used to simulate cardiac electrical activity and the body surface maps. A two-site pacing protocol was used to generate two simultaneously activated myocardial events on the anterior epicardial wall and the anterior endocardial wall. Following the pacing, the BSLMs and the body surface potential maps (BSPMs) were calculated and compared with the known activation pattern. As a result, the BSLMs showed superior resolution than the BSPMs for localized initial ventricular activity. In summary, the present study suggests that body surface Laplacian mapping may provide a useful methodology for the clinical diagnosis of cardiac electrical abnormalities.

Simulation of body surface Laplacian maps during ventricular pacing in a 3D inhomogeneous heart-torso model.

A computer simulation study has been conducted to investigate the performance of body surface Laplacian maps (BSLMs) in localizing and imaging spatially separated myocardial electrical events. A cellular automaton model of ventricles simulates cardiac electrical activity using a two-site pacing protocol to induce dual simultaneously active myocardial electrical events. The heart model is embedded in a realistically shaped inhomogeneous volume conductor. The BSLMs are numerically computed from the induced electrical activity in the heart model. The present computer simulation results show that the BSLM can provide better separation and localization of two regional myocardial electrical events as compared with the body surface potential map (BSPM).

Modified extraperitoneal approach to the abdominal aorta in exposure of the thoracoabdominal aorta.

A modified left transthoracic and retroperitoneal approach to the thoracoabdominal aorta without entering the peritoneal cavity is reported. The advantage of this modification is that the abdominal wall musculature is preserved intact except for the division of a small part of the transversus abdominis muscle.

Development of a non-invasive treatment system for urinary incontinence using a functional continuous magnetic stimulator (FCMS).

A system composed of a functional continuous magnetic stimulator (FCMS) and a saddle-type coil has been developed for non-invasive treatment of urinary incontinence, especially stress incontinence and urge incontinence. The FCMS conditions were as follows: 2 kW maximum electrical power consumption, 800 V maximum capacitor voltage, 720 microseconds pulsewidth (180 microseconds rise time), and 5-30 Hz frequency. A frequency between 5 and 10 Hz is used to treat urge incontinence and a frequency between 25 Hz and 30 Hz is used to treat stress incontinence. The coil (120 mm long, 90 mm wide and 50 mm thick) fits the most suitable region for this treatment, the region from the anus to the perineum. The coil is cooled to maintain a coil temperature between 20 and 25 degrees C so that it can be used efficiently and safely. In experiments with anaesthetised dogs, it was confirmed that the urethral pressure increased when the circumference of the perineum received continuous magnetic stimulation of 720 microseconds pulsewidth (180 microseconds rise time), 10 Hz frequency and about 520 V capacitor voltage. This result suggests that magnetic stimulation can be effective as a urinary incontinence therapy.

Outcome of arthrocentesis for temporomandibular joint with closed lock at 3 years follow-up.

OBJECTIVE: The aim of this study was to evaluate the intermediate term results of arthrocentesis for the management of temporomandibular joint closed lock. STUDY DESIGN: Twenty consecutive patients with closed locking of their temporomandibular joint were treated by arthrocentesis. All patients rated their pain level on a visual analogue scale, and completed pain, jaw dysfunction, and daily activity questionnaires before, 6 months, and 3 years after the procedure. The patients' jaw opening was also scaled. Preoperative and postoperative differences of the data were analyzed statistically. The success rate was also calculated according to our success criteria. RESULTS: The success rate was 70% at 6 months follow-up; it increased to 78.9% over the 3 years of follow-up. All posttreatment scores showed significant improvements in efficacy. CONCLUSION: Arthrocentesis was considered as an effective minimally invasive surgical treatment for temporomandibular joint closed lock based when evaluated 3 years after the procedure.

Short-term treatment outcome study for the management of temporomandibular joint closed lock. A comparison of arthrocentesis to nonsurgical therapy and arthroscopic lysis and lavage.

OBJECTIVE: The aim of this study is to compare the clinical short-term results and efficacy of arthrocentesis with those of nonsurgical treatments and arthroscopic surgery for the management of temporomandibular joint closed lock. STUDY DESIGN: The three groups consisted of 63 consecutive patients treated nonsurgically, 20 patients treated with arthrocentesis, and 25 patients treated with arthroscopic surgery. All patients rated their pain level on a visual analogue scale and completed a pain, jaw dysfunction, and activity-limiting questionnaire before and 6 months after the procedure. Each patient's jaw opening was also scaled. The success rate of each procedure was calculated according to our success criteria. The clinical efficacy of each procedure was evaluated in successfully treated subgroups in which the between-group and within-group differences of the obtained data were statistically tested. RESULTS: The success rate was 55.6% in the nonsurgically treated group, 70% in the arthrocentesis group, and 91% in the arthroscopy group. With respect to efficacy, all posttreatment scores showed significant improvements in within-group differences, but no between-group differences were found between the arthrocentesis group and the other two groups. CONCLUSION: Arthrocentesis was considered as an intervening treatment modality between nonsurgical treatment and arthroscopic surgery on the basis of its short-term outcome. Although the treatment efficacy was comparable with arthroscopic surgery, this procedure was thought to be indicated for the patients with acute temporomandibular joint closed lock who were refractory to medication and mandibular manipulation rather than the alternative of arthroscopic surgery.

Preventive equipment for urinary incontinence: a device employing lower abdominal impendance changes.

The object of this work was to develop a monitoring device for measuring the volume of urine in the bladder to signal, in advance, the need to urinate and thus help prevent urinary incontinence. A high-frequency electric current of 50 KHz transmitter was applied to a pair of terminals placed on the surface of a human body. The constant current was 2mA (p-p). A pair of voltage electrodes was placed in the path of the electric current to pick up high-frequency voltage signals. The best position for current electrodes was found to be on the surface of both femoral joints. Positioning the voltage electrode above the bladder on the lower abdomen was most efficient for detecting the volume of urine. New current electrodes sutured onto underpants were fitted on the surface above the femoral joints, which did not shift in the case of movement by the subjects. The reproducibility and stability were remarkably good with this electrode. The alarm level which foretold both maximum storage volume and maximum desire to void was examined. After that, when the alarm level was set within the range of impedance charge, 60% to 70%, the possibility of prediction of urination exists.