Extended lymph-node dissection for gastric cancer

BACKGROUND: Curative resection is the treatment of choice for gastric cancer, but it is unclear whether this operation should include an extended (D2) lymph-node dissection, as recommended by the Japanese medical community, or a limited (D1) dissection. We conducted a randomized trial in 80 Dutch hospitals in which we compared D1 with D2 lymph-node dissection for gastric cancer in terms of morbidity, postoperative mortality, long-term survival, and cumulative risk of relapse after surgery. METHODS: Between August 1989 and July 1993, a total of 996 patients entered the study. Of these patients, 711 (380 in the D1 group and 331 in the D2 group) underwent the randomly assigned treatment with curative intent, and 285 received palliative treatment. The procedures for quality control included instruction and supervision in the operating room and monitoring of the pathological results. RESULTS: Patients in the D2 group had a significantly higher rate of complications than did those in the D1 group (43 percent vs. 25 percent, P<0.001), more postoperative deaths (10 percent vs. 4 percent, P= 0.004), and longer hospital stays (median, 16 vs. 14 days; P<0.001). Five-year survival rates were similar in the two groups: 45 percent for the D1 group and 47 percent for the D2 group (95 percent confidence interval for the difference, -9.6 percent to +5.6 percent). The patients who had R0 resections (i.e., who had no microscopical evidence of remaining disease), excluding those who died postoperatively, had cumulative risks of relapse at five years of 43 percent with D1 dissection and 37 percent with D2 dissection (95 percent confidence interval for the difference, -2.4 percent to +14.4 percent). CONCLUSIONS: Our results in Dutch patients do not support the routine use of D2 lymph-node dissection in patients with gastric cancer.     

The neural correlates of the awe experience: Reduced default mode network activity during feelings of awe

In the present fMRI study, we aimed to obtain insight into the key brain networks involved in the experience of awe—a complex emotion that is typically elicited by perceptually vast stimuli. Participants were presented with awe‐eliciting, positive and neutral videos, while they were instructed to get fully absorbed in the scenery or to count the number of perspective changes. By using a whole‐brain analysis we found that several brain regions that are considered part of the default mode network (DMN), including the frontal pole, the angular gyrus, and the posterior cingulate cortex, were more strongly activated in the absorption condition. But this was less the case when participants were watching awe videos. We suggest that while watching awe videos, participants were deeply immersed in the videos and that levels of self‐reflective thought were as much reduced during the awe videos, as during the perspective counting condition. In contrast, key regions of the fronto‐parietal network (FPN), including the supramarginal gyrus, the medial frontal gyrus, and the insula, were most strongly activated in the analytical condition when participants were watching awe compared to positive and neutral videos. This finding underlines the captivating, immersive, and attention‐grabbing nature of awe stimuli that is considered to be responsible for reductions in self‐reflective thought. Together these findings suggest that a key feature of the experience of awe is a reduced engagement in self‐referential processing, in line with the subjective self‐report measures (i.e., participants perceived their self to be smaller).     

Effects of stabilizers on the destabilization of proteins upon adsorption to aluminum salt adjuvants

Excipients for protein-based vaccines are currently identified by evaluating the stability of the protein in solution. In most cases, however, the protein is adsorbed to the surface of an aluminum salt adjuvant in the final vaccine formulation. Previous studies showed that model protein antigens may be structurally altered and less thermally stable upon adsorption to aluminum salt adjuvants [Jones LS, Peek LJ, Power J, Markham A, Yazzie B, Middaugh CR, 2005, J Biol Chem 280:13406-13414]. The work presented herein provides evidence that compounds that stabilize the protein in solution also stabilize the adsorbed protein; however, the stability of the adsorbed protein in the presence of the stabilizer remains lower than that of the protein in solution. Potential implications of the reduced stability on the approach used to select excipients during formulation development are discussed.     

Metabolism of arsenic in Drosophila melanogaster and the genotoxicity of dimethylarsinic acid in the Drosophila wing spot test

Inorganic arsenic is nongenotoxic in the Drosophila melanogaster wing somatic mutation and recombination test (SMART). Recent evidence in mammalian systems indicates that methylated metabolites of arsenic are more genotoxic than inorganic arsenic. Thus, we hypothesized that inorganic arsenic is nongenotoxic in Drosophila because they are unable to biotransform arsenic to methylated forms. In the present study, we fed trivalent and pentavalent inorganic arsenic to Drosophila larvae and adults and measured the production of methylated derivatives. No biomethylated arsenic species were found in the organisms or in the growth medium, which suggests that Drosophila are unable to biomethylate inorganic arsenic. Exposure of Drosophila to the methylated arsenic derivative dimethylarsinic acid (DMA(V)) resulted in incorporation of this organoarsenic compound without demethylation. In addition, we used the SMART wing spot assay, which measures loss of heterozygosity (LOH) resulting from gene mutation, chromosomal rearrangement, chromosome breakage, and chromosome loss, to evaluate the genotoxicity of DMA. DMA by itself induced significant increases in the frequency of total spots, small spots, and large single spots. These results are consistent with the important role of arsenic biomethylation as a determinant of the genotoxicity of arsenic compounds. The absence of biomethylation in Drosophila could explain the lack of genotoxicity for inorganic arsenic and the genotoxicity of methylated arsenic species in the SMART wing spot assay.     

Schistosomin: a pronase-sensitive agent in the hemolymph of Trichobilharzia ocellata-infected Lymnaea stagnalis inhibits the activity of albumen glands in vitro

The schistosome parasite, Trichobilharzia ocellata, nearly completely inhibits the reproductive activity of its intermediate host, Lymnaea stagnalis. The synthetic activity of albumen glands of infected snails at day 35 postinfection (p.i.) is only 1% of the control value. The parasite acts by humoral means. We tested the hypothesis that (a) specific humoral agent(s) is (are) involved and refer to this (these) agent(s) as schistosomin. The presence of schistosomin in the hemolymph of infected snails was investigated by using galactogen synthesis in albumen glands as an in vitro bioassay. The synthetic activity of albumen glands of noninfected snails decreased by about 50% during a 1-h incubation in the hemolymph of infected snails. This inhibition is attributed to schistosomin. Based on these results, with the present bioassay schistosomin appears in the hemolymph between days 28–36 p.i. onwards. Schistosomin is heat-stable (100 C) and pronase-sensitive, and therefore it might have a peptide nature. Schistosomin suppresses the stimulating action of the female, gonadotrophic dorsal body hormone at relatively low doses, which suggests that it may compete with this hormone for the same receptors. The development of two other bioassays for schistosomin in our laboratory is discussed.     

Genotoxicity modulation by cadmium treatment: studies in the Drosophila wing spot test

The genotoxic activity of cadmium chloride (CC) has been evaluated in the somatic mutation and recombination test (SMART) in Drosophila melanogaster. In addition, its possible modulating effect on the genotoxicity of two known mutagenic agents, potassium dichromate (PDC) and ethyl methanesulfonate (EMS), was investigated. Three different types of combined treatments of CC with the two genotoxins were performed: pretreatment, cotreatment, and posttreatment. The SMART assay is based on the principle that loss of heterozygosity for the recessive markers, multiple wing hairs (mwh) and flare-3 (flr(3)), leads to the formation of mutant clones in the imaginal disks of larvae, which are expressed as mutant spots on the wings of adult flies. Thus, after adult emergence, the wings of the adult flies were scored for the presence of single and/or twin spots. Our results show that CC alone was not effective in increasing the frequency of any of the three categories of spots (small, large, and twin). In the cotreatment experiments, CC increased the genotoxicity of PDC but it decreased the genotoxicity of EMS. No effects of CC were observed in the pretreatment or posttreatment experiments; however, only low concentrations of CC, PDC, and EMS were tested in the pretreatment assays due to the high toxicity of the treatment. Although our results with PDC are consistent with the hypothesis that cadmium can interfere with repair mechanisms, the EMS data suggest that other modulating mechanisms are also involved in the genotoxicity of this metal.     

Modulation of nicotinic acetylcholine receptor function in bovine adrenal chromaffin cells by thymopentin

Thymopentin is a five amino acid peptide which corresponds to amino acids 32–36 of the thymic polypeptide thymopoietin. Previous work had shown that TP-5 could modulate responsiveness at the muscle-type nicotinic receptor. The present studies show that neuronal nicotinic receptor function, measured as radiolabelled noradrenaline release from bovine adrenal medullary cells, was attenuated by thymopentin. The pentapeptide exhibited specificity for nicotinic receptor evoked release, since thymopentin did not affect potassium-stimulated secretion of [³H]noradrenaline. It appears, therefore, that thymopentin antagonizes catecholamine release by specifically modulating nicotinic receptor responsiveness.     

Effects of processing and storage conditions on amyloid beta (1-42) and tau concentrations in cerebrospinal fluid: implications for use in clinical practice

BACKGROUND: Reported concentrations of amyloid beta (1-42) (A beta 42) and tau in cerebrospinal fluid (CSF) differ among reports. We investigated the effects of storage temperature, repeated freeze/thaw cycles, and centrifugation on the concentrations of A beta 42 and tau in CSF. METHODS: Stability of samples stored at -80 degrees C was determined by use of an accelerated stability testing protocol according to the Arrhenius equation. A beta 42 and tau concentrations were measured in CSF samples stored at 4, 18, 37, and -80 degrees C. Relative CSF concentrations (%) of the biomarkers after one freeze/thaw cycle were compared with those after two, three, four, five, and six freeze/thaw cycles. In addition, relative A beta 42 and tau concentrations in samples not centrifuged were compared with samples centrifuged after 1, 4, 48, and 72 h. RESULTS: A beta 42 and tau concentrations were stable in CSF when stored for a long period at -80 degrees C. CSF A beta 42 decreased by 20% during the first 2 days at 4, 18, and 37 degrees C compared with -80 degrees C. CSF tau decreased after storage for 12 days at 37 degrees C. After three freeze/thaw cycles, CSF A beta 42 decreased 20%. CSF tau was stable during six freeze/thaw cycles. Centrifugation did not influence the biomarker concentrations. CONCLUSIONS: Repeated freeze/thaw cycles and storage at 4, 18, and 37 degrees C influence the quantitative result of the A beta 42 test. Preferably, samples should be stored at -80 degrees C immediately after collection.