Retrospective comparison of infusional 5-fluorouracil, doxorubicin, and mitomycin-C (modified FAM) combination chemotherapy versus palliative therapy in treatment of advanced gastric cancer

About one-third of patients with gastric cancer are unresectable at the time of diagnosis. Their median survival is < 6 months, with a grave prognosis. The purpose of this study was to assess the efficacy of a modified FAM (mFAM) regimen in advanced gastric cancer. We retrospectively reviewed the clinical records of 409 advanced gastric cancer patients who had not received curative surgery. Among 409 patients, 202 patients were treated with an mFAM regimen (infusional 5-FU + doxorubocin + mitomycin-C), and 207 patients received no chemotherapy (control group). No differences were found in clinical parameters between the two groups. The 1-year survival rates were 34.1% for the mFAM-treated group and 22.5% for the control group (p = 0.0135). In subset analysis, a higher 1-year survival rate was demonstrated in patients with mFAM and palliative surgery. Of the 154 evaluable patients in the mFAM-treated group, the response rate was 17.5%. In these patients, median response duration was 30 weeks, and progression-free survival was 23 weeks. Overall toxicity of mFAM regimen was relatively tolerable and reversible. In conclusion, FAM combination chemotherapy, which has been used as a standard therapy, prolonged survival after modification of the administration schedule and combination with palliative surgery. A prospective randomized study is warranted to confirm this conclusion from our retrospective study.     

High-resolution crystal structures of delta5-3-ketosteroid isomerase with and without a reaction intermediate analogue

Bacterial Delta5-3-ketosteroid isomerase (KSI) catalyzes a stereospecific isomerization of steroid substrates at an extremely fast rate, overcoming a large disparity of pKa values between a catalytic residue and its target. The crystal structures of KSI from Pseudomonas putida and of the enzyme in complex with equilenin, an analogue of the reaction intermediate, have been determined at 1.9 and 2.5 A resolution, respectively. The structures reveal that the side chains of Tyr14 and Asp99 (a newly identified catalytic residue) form hydrogen bonds directly with the oxyanion of the bound inhibitor in a completely apolar milieu of the active site. No water molecule is found at the active site, and the access of bulk solvent is blocked by a layer of apolar residues. Asp99 is surrounded by six apolar residues, and consequently, its pKa appears to be elevated as high as 9.5 to be consistent with early studies. No interaction was found between the bound inhibitor and the residue 101 (phenylalanine in Pseudomonas testosteroni and methionine in P. putida KSI) which was suggested to contribute significantly to the rate enhancement based on mutational analysis. This observation excludes the residue 101 as a potential catalytic residue and requires that the rate enhancement should be explained solely by Tyr14 and Asp99. Kinetic analyses of Y14F and D99L mutant enzymes demonstrate that Tyr14 contributes much more significantly to the rate enhancement than Asp99. Previous studies and the structural analysis strongly suggest that the low-barrier hydrogen bond of Tyr14 (>7.1 kcal/mol), along with a moderate strength hydrogen bond of Asp99 ( approximately 4 kcal/mol), accounts for the required energy of 11 kcal/mol for the transition-state stabilization.     

Low-frequency suppression of auditory nerve responses to characteristic frequency tones

The effects of low-frequency (50, 100, 200 and 400 Hz) 'suppressor' tones on responses to moderate-level characteristic frequency (CF) tones were measured in chinchilla auditory nerve fibers. Two-tone interactions were evident at suppressor intensities of 70-100 dB SPL. In this range, the average response rate decreased as a function of increasing suppressor level and the instantaneous response rate was modulated periodically. At suppression threshold, the phase of suppression typically coincided with basilar membrane displacement toward scala tympani, regardless of CF. At higher suppressor levels, two suppression maxima coexisted, synchronous with peak basilar membrane displacement toward scala tympani and scala vestibuli. Modulation and rate-suppression thresholds did not vary as a function of spontaneous activity and were only minimally correlated with fiber sensitivity. Except for fibers with CF < 1 kHz, modulation and rate-suppression thresholds were lower than rate and phase-locking thresholds for the suppressor tones presented alone. In the case of high-CF fibers with low spontaneous activity, excitation thresholds could exceed suppression thresholds by more than 30 dB. The strength of modulation decreased systematically with increasing suppressor frequency. For a given suppressor frequency, modulation was strongest in high-CF fibers and weakest in low-CF fibers. The present findings strongly support the notion that low-frequency suppression in auditory nerve fibers largely reflects an underlying basilar membrane phenomenon closely related to compressive non-linearity.     

The number of glutamate transporter subtype molecules at glutamatergic synapses: chemical and stereological quantification in young adult rat brain

The role of transporters in shaping the glutamate concentration in the extracellular space after synaptic release is controversial because of their slow cycling and because diffusion alone gives a rapid removal. The transporter densities have been measured electrophysiologically, but these data are from immature brains and do not give precise information on the concentrations of the individual transporter subtypes. Here we show by quantitative immunoblotting that the numbers of the astroglial glutamate transporters GLAST (EAAT1) and GLT (EAAT2) are 3200 and 12,000 per micrometer3 tissue in the stratum radiatum of adult rat hippocampus (CA1) and 18,000 and 2800 in the cerebellar molecular layer, respectively. The total astroglial cell surface is 1.4 and 3.8 m2/cm3 in the two regions, respectively, implying average densities of GLAST and GLT molecules in the membranes around 2300 and 8500 micrometer-2 in the former and 4700 and 740 micrometer-2 in the latter region. The total concentration of glial glutamate transporters in both regions corresponds to three to five times the estimated number of glutamate molecules in one synaptic vesicle from each of all glutamatergic synapses. However, the role of glial glutamate transporters in limiting synaptic spillover is likely to vary between the two regions because of differences in the distribution of astroglia. Synapses are completely ensheathed and separated from each other by astroglia in the cerebellar molecular layer. In contrast, synapses in hippocampus (stratum radiatum) are only contacted by astroglia and are often found side by side without intervening glial processes.     

Proportions of volatile fatty acids in relation to the chemical composition of feeds based on grass silage

This experiment was designed to quantify the relationships between feed chemistry and the proportions of rumen volatile fatty acids (VFA) across a wide range of feedstuffs. In an experiment using 11 rumencannulated sheep, 16 test feeds were fed at three different inclusion rates in rations that were based on grass silage. The 17 periods of the experiment were each 14 d long. Eight rumen samples were taken every 24 h on d 13 and 14 of each period from which the mean daily proportions of VFA were derived. The effects of an increase in the proportion of test feed in the total feed on proportions of VFA were significant. The observed proportions of VFA were related to the chemical composition of the total feed by principal component regression. The inclusion of the amount of feed offered and the ratio of test feed to total feed in these regressions did not improve their precision; these terms were not significant. The significant terms in the regressions were crude protein, starch, sugar, and cellulose (calculated by difference). The R2 values achieved for the regressions between acetate, propionate, and butyrate (molar proportions) and feed composition were 77.5, 68.0, and 87.3%, respectively. These regressions provided an apparently robust basis for predicting molar proportions of VFA from feed chemistry in feeds based on grass silage.     

Laryngeal atresia or stenosis presenting as second-trimester fetal ascites--diagnosis and pathology in three independent cases

Congenital atresia of the larynx is a rare abnormality. We describe three cases where prenatal diagnosis during the second trimester showed massive abdominal fetal ascites and at post-mortem, laryngeal atresia was identified in two cases, and severe laryngeal stenosis in the third. All were associated with pulmonary hyperplasia. No additional abnormalities were found in other systems. Overdistended lung tissue and ascites are resultant from aberrant laryngeal growth; laryngeal anomalies are a cause of isolated fetal ascites. The association of ascites and voluminous lungs should arouse suspicion of laryngeal atresia and should be an indication for careful pathological study of the fetal larynx.     

The effects of dexamethasone immunosuppression on turkey osteomyelitis complex in an experimental Escherichia coli respiratory infection

The results of a field trial conducted in Latin America with two indirect enzyme-linked immunosorbent assays (ELISAs) and two competitive ELISAs (CELISAs) for the detection of bovine antibody to Brucella abortus are reported. One of the CELISA formats performed most accurately. The percentage of positive reactions in the CELISA relative to the selected positive rose bengal agglutination test (RBT) and complement fixation test (CFT) results was 97.47%, the percentage of negatives relative to the selected negative RBT and CFT results for unexposed cattle was 98.32%, and the percentage of negatives in cattle vaccinated with B. abortus 19 was 96.51%. The same assay format under Canadian conditions had an actual sensitivity of 100%, a specificity of 99.90% in nonvaccinates, and a specificity of 97.7% in a strain 19-vaccinated population. Overall, the CELISA performed as expected and the results were not dissimilar from the results obtained in the Canadian study. This provided further evidence that this CELISA can in many instances differentiate infected cattle from those that are vaccinated or infected with a cross-reacting organism while still giving very few false-positive or false-negative results.