The role of neoadjuvant therapy in surgically resectable esophageal cancer

OBJECTIVE: To determine the effect of neoadjuvant therapy (NT) (preoperative chemotherapy, radiation therapy, or both) in surgically resectable esophageal cancer. DESIGN: A retrospective review over a 20-year period. SETTING: A tertiary academic medical center. PARTICIPANTS: All patients undergoing surgical resection for esophageal cancer (N = 316) over this time period. MAIN OUTCOME MEASURES: Perioperative morbidity and mortality, local and distant recurrences, and overall survival. RESULTS: Patients undergoing NT (n = 106) had prognostic factors similar to those treated with surgery alone (n = 210). No increase was noted in surgical morbidity with NT (anastomotic leaks, reoperation rates, complications, or extended hospital stays). Overall survival was not improved by NT (median survival, 14 months) except in the subset of patients (11/83) who responded completely (100% histological necrosis) to preoperative chemotherapy (median survival, 79.2 months; P < .02). Complete response to radiation therapy alone was not associated with improved survival. Partial necrosis of the primary tumor was seen in 13 (15%) of 83 patients but conferred no survival advantage. Complete response to preoperative chemotherapy was associated with squamous cell pathological features and excellent performance status as measured by preanesthesia evaluation. CONCLUSIONS: The addition of NT did not increase perioperative morbidity or mortality. Only the subset of patients who had a complete response to preoperative chemotherapy showed a survival advantage. Excellent performance status and squamous cell pathological features were associated with an increased chance of complete pathological response following preoperative chemotherapy.     

The Arabidopsis thaliana ACT4/ACT12 actin gene subclass is strongly expressed throughout pollen development

We analyzed the displacement activity of sarpogrelate and its active metabolite (M-1) in the radiolabeled ligand binding to various 5-hydroxytryptamine (5-HT) receptor subtypes using rat brain cortical membranes. Sarpogrelate was shown to have the same affinity as ritanserin for 5-HT2A receptors, with a Ki value of 8.39 nM. The active metabolite of sarpogrelate, M-1, was more active than sarpogrelate itself and of ritanserin, with a Ki value of 1.70 nM. Both sarpogrelate and M-1 had no affinity for 5-HT1A receptors, but these substances, at a concentration of 10 microM, displaced the specific binding to the 5-HT1B receptors of [125I]iodocyanopindolol, resulting in Ki values of 0.881 and 0.859 microM, respectively. The Ki values of sarpogrelate and M-1 are almost the same as that of ritanserin, a specific 5-HT2 receptor antagonist. Sarpogrelate and M-1, as well as ritanserin, are shown to have very low affinity for 5-HT1B receptors. Both sarpogrelate and M-1 had no affinity for 5-HT3 receptor subtypes. In the 5-HT4 receptor binding experiments, sarpogrelate exhibited almost no affinity, while M-1, at the concentration of 10 microM, displaced the binding activity, resulting in a Ki value of 0.838 microM. Both drugs had a weak antagonistic effect on a 5-HT4 receptor-mediated function, i.e., the 5-HT-induced relaxation of rat isolated esophageal tunica muscularis mucosae. In conclusion, sarpogrelate and M-1 have high affinity for 5-HT2A receptors with a relatively high selectivity.     

Porphyromonas gingivalis genes isolated by screening for epithelial cell attachment

Porphyromonas gingivalis is associated with chronic and severe periodontitis in adults. P. gingivalis and the other periodontal pathogens colonize and interact with gingival epithelial cells, but the genes and molecular mechanisms involved are unknown. To dissect the first steps in these interactions, a P. gingivalis expression library was screened for clones which bound human oral epithelial cells. Insert DNA from the recombinant clones did not contain homology to the P. gingivalis fimA gene, encoding fimbrillin, the subunit protein of fimbriae, but showed various degrees of homology to certain cysteine protease-hemagglutinin genes. The DNA sequence of one insert revealed three putative open reading frames which appeared to be in an operon. The relationship between P. gingivalis attachment to epithelial cells and the activities identified by the screen is discussed.     

Morphometric studies of the aged hippocampus: I. Volumetric analysis in behaviorally characterized rats

The present investigation examined the structural integrity of the aged hippocampus by using computer-aided morphometry to quantify the volume of principal hippocampal circuits in young, mature adult, and aged Long-Evans rats. A key feature of the experimental design was that the status of hippocampal-dependent learning and memory was documented prior to histologic evaluation. The following regions, which were visualized by using Timm staining, were included in the analysis: 1) outer portions of the dentate gyrus molecular layer (OML) innervated by the lateral entorhinal cortex, 2) middle portions of the molecular layer (MML) that receive input from the medial entorhinal cortex, 3) the commissural/associational zone (IML) immediately adjacent to the granule cell layer, and 4) the hilus and mossy fiber projection to the CA3 pyramidal cell field (MF). To identify morphometric changes that emerge during the same segment of the life span as age-related learning impairment, analysis of the volumetric results focused on comparisons between the mature adult group and the aged group. Among the individual regions that were analyzed, age-related decreases in total volume were restricted to the MML. This effect, however, occurred against a background of other, subtle changes that, together, reflected substantial reorganization in the normal balance of hippocampal circuitry. Age-related decreases in the proportion of the molecular layer (ML) that comprises the MML were accompanied by a corresponding increase in relative IML volume. The ratio between the volumes of the MML and the MF also displayed significant age-related decline. Overall, aging affected septal levels of the hippocampus disproportionately, and, with the exception of MML/MF volume ratio, the temporal hippocampus was spared. Finally, the status of spatial learning among the aged animals correlated selectively with decreases in the MML/ML and MML/MF ratios. These results demonstrate that the effects of aging are regionally selective and circuit specific, and they suggest that connectional reorganization may contribute to age-related decline in the computational functions of the hippocampus.     

Atrial natriuretic peptide and oxytocin induce natriuresis by release of cGMP

Our hypothesis is that oxytocin (OT) causes natriuresis by activation of renal NO synthase that releases NO followed by cGMP that mediates the natriuresis. To test this hypothesis, an inhibitor of NO synthase, L-nitroarginine methyl ester (NAME), was injected into male rats. Blockade of NO release by NAME had no effect on natriuresis induced by atrial natriuretic peptide (ANP). This natriuresis presumably is caused by cGMP because ANP also activates guanylyl cyclase, which synthesizes cGMP from GTP. The 18-fold increase in sodium (Na+) excretion induced by OT (1 microgram) was accompanied by an increase in urinary cGMP and preceded by 20 min a 20-fold increase in NO3- excretion. NAME almost completely inhibited OT-induced natriuresis and increased NO3- excretion; however, when the dose of OT was increased 10-fold, a dose that markedly increases plasma ANP concentrations, NAME only partly inhibited the natriuresis. We conclude that the natriuretic action of OT is caused by a dual action: generation of NO leading to increased cGMP and at higher doses release of ANP that also releases cGMP. OT-induced natriuresis is caused mainly by decreased tubular Na+ reabsorption mediated by cGMP. In contrast to ANP that releases cGMP in the renal vessels and the tubules, OT acts on its receptors on NOergic cells demonstrated in the macula densa and proximal tubules to release cGMP that closes Na+ channels. Both ANP- and OT-induced kaliuresis also appear to be mediated by cGMP. We conclude that cGMP mediates natriuresis and kaliuresis induced by both ANP and OT.     

The role of the Cys191-Cys220 disulfide bond in trypsin: new targets for engineering substrate specificity

The S1 binding site of trypsin is cross-linked by the conserved Cys191- Cys220 disulfide bond. The substitution of Cys191 and Cys220 with Ala decreases the activity of trypsin by 20-200-fold as measured by kcat/K(m) for the hydrolysis of amide substrates; in contrast, ester hydrolysis is decreased by < 10-fold. Similar decreases are observed in the hydrolysis of oligopeptide and single amino acid substrates. This decrease in activity results from a decrease in the acylation rate. The substrate binding and deacylation rate are not affected by the loss of the disulfide bond. C191A/C220A binds BPTI with the same affinity as trypsin, although the affinity of benzamidine is decreased 10-fold and the affinity of leupeptin is decreased 1000-fold. The CD spectrum of C191A/C220A displays significant differences from that of trypsin; these differences most likely result from the loss of the disulfide chromophore, although perturbation of enzyme structure cannot be discounted. The loss of the Cys191-Cys220 disulfide has no effect on the stability of trypsin as measured by urea denaturation. Single and double substitutions of Ser at positions 191 and 220 have a similar activity to C191A/C220A. These results indicate that the Cys191-Cys220 disulfide bond is not essential for the function, structure or stability of trypsin.      

The success of dietary protein restriction in alkaptonuria patients is age-dependent

Alkaptonuria is characterized by an increased urinary excretion of homogentisic acid, pigmentation of cartilage and connective tissues, and ultimately the development of inflammatory arthropathy. Various diets low in protein have been designed to decrease homogentisic acid excretion and to prevent the ochronotic pigmentation and arthritic lesions. However, limited information is available on the long-term beneficial effects of these diets. We reviewed the medical records of 16 patients aged 3-27 years (4 > 18 years) to ascertain the age of diagnosis, growth, development, social behaviour, signs of complications and longitudinal dietary compliance. The diagnosis of alkaptonuria was made at an average age of 1.4 years (2 months-4 years); following the diagnosis all patients were prescribed a diet with a protein content of 1.5 g/kg per day. All patients showed normal growth and development, and no major complications of the disease. Behavioural problems associated with poor dietary compliance emerged as the main problem. Dietary compliance decreased progressively with age. The effect of dietary protein restriction in homogentisic acid excretion was studied by fixing the amounts of protein in the diet at 1 g/kg per day and 3.5-5 g/kg per day during 8 days. Twelve patients, aged 4-27 years, participated in the investigation. Protein restriction resulted in a significantly lower excretion of homogentisic acid in the urine of children younger than 12 years (p < 0.01), whereas this effect was less obvious for adolescent and adult patients. The results suggest that restriction of protein intake may have a beneficial effect on alkaptonuric children; but continuation of this regimen to older age seems questionable and not practical.     

The quantitative analysis of glass by emission spectrography: a six element survey

During two dive series, one to 132 fsw and one to 210 fsw, Doppler ultrasonic bubble detectors were used to monitor venous gas bubbles in divers during decompression and for 30 min thereafter. Various decompression schedules were used. Bubble scores were evaluated by independent listerners to tape recordings in a blind manner. A significant increase in bubble scores throughout the stages of decompression and postdecompression was demonstrated as well as a statistically significant relationship between bubble score and decompression sickness. A reduction in mean bubble score was found in divers who made an additional deep decompression stop that was unrelated to the extension of the decompression time. The implications of these findings are discussed.     

Does concurrent or prior nicotine exposure interact with neonatal hypoxia to produce cardiac cell damage?

Cigarette smoking during pregnancy exposes the fetus to both nicotine and hypoxia/ischemia; postnatal exposure to second-hand smoke also involves substances that cause hypoxia (CO, HCN). Although developing cardiac cells are more resistant to hypoxia-induced damage than are mature cells, we examined whether nicotine affects this resistance, either when exposure is concurrent with hypoxia, or when animals are exposed to nicotine prenatally and receive subsequent hypoxic exposure. One, 8-, or 15-day-old rats exposed to 7% O2 for 2 hr all showed inhibition of cardiac DNA synthesis. By contrast, administration of nicotine at either low (0.3 mg/kg) or high (3 mg/kg) doses failed to alter DNA synthesis. To examine effects on cells that were not undergoing mitosis, we examined ornithine decarboxylase (ODC), an enzymatic marker for cell damage. One day old rats showed inhibition of ODC by hypoxia, a response that represents preservation of cell integrity; by 8 days of age, ODC was increased by hypoxia, evidence of cell damage. The high dose of nicotine evoked an increase in ODC at all ages and the low dose exacerbated the effects of hypoxia at 8 days of age. Prenatal nicotine exposure caused a transient inhibition of cardiac DNA synthesis but did not produce evidence of cell damage (ODC, protein synthesis markers) by itself, nor did it alter the effect of a subsequent postnatal exposure to hypoxia. These results suggest that cardiac cell damage could emerge as a consequence of concurrent, repeated exposures to nicotine and hypoxia. Such effects could contribute to the elevated incidence of perinatal morbidity/mortality and Sudden Infant Death Syndrome associated with smoking.     

Review article: the development of atrophic gastritis--Helicobacter pylori and the effects of acid suppressive therapy

Helicobacter pylori is uniquely adapted to survival in the strongly acidic gastric lumen. In vitro, both acid and certain acid suppressors affect bacterial growth. In vivo, there is little evidence that acid suppressors have any effect on bacterial survival. In contrast, decrease of acid secretion quickly leads to a spreading of the bacterial infection throughout the body and fundus of the stomach, which is accompanied by an increase of the associated gastritis. Helicobacter pylori gastritis may, in a substantial number of infected subjects, ultimately lead to atrophy and intestinal metaplasia, conditions with an increased risk for gastric cancer. This review summarizes the data on the interrelation between Helicobacter pylori, gastric acid secretion and development of atrophic gastritis.