Fractional allelic loss in gastric carcinoma correlates with growth patterns

To gain an insight into the genetic events underlying morphological phenotypes, we analysed 58 gastric carcinoma tissues for the genome-wide allelotype study using microsatellite markers. Based on a binomial distribution, loss of heterozygosity (LOH) that was significantly more frequent than expected (P<0.05) thus interpreted as nonrandom LOH selected during tumorigenesis. The overall extent of chromosomes undergoing LOH i.e. fractional allelic loss (FAL, the ratio of LOH-positive markers to the total number of informative markers) was measured in each tumor patient. Nonrandom LOH was found on 17p (48.0%), 18q (38.4%), 13q (38.1%) and 9p (36.4%). Overall, there were no significant phenotypes correlated with allelic loss on specific chromosome regions. Based on a bimodal distribution of FAL values with two peaks bordered by a mean of 0.233, tumors were classified into LOH-related (>0.233) and LOH-unrelated (<0.233) types. Among 24 patients with LOH-related tumors, increase in the infiltrative type of growth pattern was found to correspond with a significant trend of increasing FAL values. This study shows that the growth pattern of gastric carcinoma is correlated with FAL, suggesting that a malignant phenotype is influenced by LOH event.     

Procedural results and late clinical outcomes after placement of three or more stents in single coronary lesions

BACKGROUND: Previous reports have suggested higher procedural and long-term complications among patients treated with multiple stents for diffuse lesions and/or long dissections. METHODS AND RESULTS: To evaluate procedural success, major complications, and clinical outcomes (> or = 1 year) in a consecutive series of patients treated with multiple (> or = 3) contiguous stents in single lesions, we evaluated in-hospital and long-term (1-year) clinical outcomes in 117 consecutive patients treated with > or = 3 coronary stents compared with a concurrent series of patients treated with 1 or 2 stents (n=1673) between January 1, 1994, and December 31, 1995. Multiple stents were implanted more often in larger vessels, in the right coronary artery or saphenous vein grafts, and for unfavorable lesion characteristics, including long (>20 mm), calcified, ulcerated, thrombotic, and/or flow-obstructing lesions. Overall procedural success was obtained in 97.4% of patients and was similar whether 1 or 2 versus > or = 3 stents were used. Non-Q-wave MI (CK-MB > or = 5 times normal) was more frequent after > or = 3 stents (22.8% versus 13.4%, P=.005). Target lesion revascularization (TLR) was 14.6% for 1 or 2 stents and 13.3% for > or = 3 stents (P=.70). There was no difference in death (2.2% versus 0.9%, P=.34) or Q-wave MI (1.4% versus 0.9%, P=.64) between the two groups (1 or 2 stents versus > or = 3 stents, respectively), and overall cardiac event-free survival was similar during follow-up (P=.70). CONCLUSIONS: Patients treated with multiple (> or = 3) contiguous stents compared with 1 or 2 stents have (1) similar in-hospital procedural success and major complications despite having more unfavorable lesion characteristics, (2) a higher rate of procedural non-Q-wave MI, and (3) similar TLR and overall major cardiac event rates during 1 year of follow-up.     

The nuclear matrix revealed by eluting chromatin from a cross-linked nucleus

The nucleus is an intricately structured integration of many functional domains whose complex spatial organization is maintained by a nonchromatin scaffolding, the nuclear matrix. We report here a method for preparing the nuclear matrix with improved preservation of ultrastructure. After the removal of soluble proteins, the structures of the nucleus were extensively cross-linked with formaldehyde. Surprisingly, the chromatin could be efficiently removed by DNase I digestion leaving a well preserved nuclear matrix. The nuclear matrix uncovered by this procedure consisted of highly structured fibers, connected to the nuclear lamina and built on an underlying network of branched 10-nm core filaments. The relative ease with which chromatin and the nuclear matrix could be separated despite extensive prior cross-linking suggests that there are few attachment points between the two structures other than the connections at the bases of chromatin loops. This is an important clue for understanding chromatin organization in the nucleus.     

Serotonergic function and negative and depressive symptomatology in schizophrenia and major depression

BACKGROUND: Serotonergic abnormalities are found in both major depressive disorder (MDD) and schizophrenia. Depressive symptoms commonly occur alongside the negative or defect symptoms in schizophrenia and antiserotonergic drugs may be particularly effective in their treatment. We wished to explore whether these symptoms could be distinguished biologically by directly comparing serotonergic function in these two illnesses. METHOD: Fifteen patients with MDD and 13 patients with schizophrenia underwent testing with the specific serotonin releasing agent D-fenfluramine (D-FEN). Prolactin and cortisol responses were measured to ascertain central serotonergic function. Individual patient results were compared with their own carefully matched control to correct for the effect of age, sex, weight and menstrual cycle, before the two patient groups were then compared. RESULTS: Prolactin responses differed significantly between the two patient groups, being lower in MDD patients and higher in schizophrenia patients than their individually matched controls. Cortisol responses did not differ. Within the schizophrenia group, increased serotonergic function correlated positively with depressive symptoms, but there was no such correlation with defect symptoms. Depressive scores were negatively correlated with the presence of negative symptoms in the schizophrenic group. CONCLUSIONS: Schizophrenia and MDD have distinct and opposite neuroendocrine responses to D-FEN. There is no evidence that depressive symptoms in these two conditions have a common serotonergic basis. Moreover, these responses distinguished between negative and depressive symptoms in our schizophrenic group.     

Effect of altered vision on constant load exercise performance while wearing a respirator

Previous testing has shown that visual acuity greatly influences task performance at light work rate levels. At moderate to heavy work rates, however, the Performance Rating Table (PRT) predicts almost no visual acuity effect. This experiment was performed to determine if the PRT value is realistic. Ten subjects walked on a treadmill at 75-80% of their maximum heart rates until their voluntary end points. Subjects wore various masks of the same kind, each with a different set of clouded lenses. Visual acuities, as measured on the Snellen eye chart, were measured before, during, and after exercise. It was found that visual acuity did not influence performance time, and that an average value for a performance rating of 91 must have been influenced by other mask factors besides visual acuity. These other factors are most likely respiratory stress, thermal stress, and other vision elements. The full-facepiece masks used in this study adversely affected visual acuity by about three-quarters of a Snellen line during exercise. Postexercise visual acuities were found to first decrease below pre-exercise values, then become better than pre-exercise values, then decline asymptotically to pre-exercise values.     

Gelsolin binding to phosphatidylinositol 4,5-bisphosphate is modulated by calcium and pH

The actin cytoskeleton of nonmuscle cells undergoes extensive remodeling during agonist stimulation. Lamellipodial extension is initiated by uncapping of actin nuclei at the cortical cytoplasm to allow filament elongation. Many actin filament capping proteins are regulated by phosphatidylinositol 4,5-bisphosphate (PIP2), which is hydrolyzed by phospholipase C. It is hypothesized that PIP2 dissociates capping proteins from filament ends to promote actin assembly. However, since actin polymerization often occurs at a time when PIP2 concentration is decreased rather than increased, capping protein interactions with PIP2 may not be regulated solely by the bulk PIP2 concentration. We present evidence that PIP2 binding to the gelsolin family of capping proteins is enhanced by Ca2+. Binding was examined by equilibrium and nonequilibrium gel filtration and by monitoring intrinsic tryptophan fluorescence. Gelsolin and CapG affinity for PIP2 were increased 8- and 4-fold, respectively, by microM Ca2+, and the Ca2+ requirement was reduced by lowering the pH from 7.5 to 7.0. Studies with the NH2- and COOH-terminal halves of gelsolin showed that PIP2 binding occurred primarily at the NH2-terminal half, and Ca2+ exposed its PIP2 binding sites through a change in the COOH-terminal half. Mild acidification promotes PIP2 binding by directly affecting the NH2-terminal sites. Our findings can explain increased PIP2-induced uncapping even as the PIP2 concentration drops during cell activation. The change in gelsolin family PIP2 binding affinity during cell activation can impact divergent PIP2-dependent processes by altering PIP2 availability. Cross-talk between these proteins provides a multilayered mechanism for positive and negative modulation of signal transduction from the plasma membrane to the cytoskeleton.     

Effect of influenza vaccine on bronchoprovocation testing in normal subjects

A study of 55 nonasthmatic patients was undertaken to determine if recent influenza vaccination is a justifiable exclusionary criteria for bronchoprovocation testing. Healthy subjects without history of asthma and with negative methacholine challenge tests were given an intramuscular injection of killed influenza vaccine. Methacholine challenge testing was repeated 24 h later. While a statistically significant decline in FEV1 at 188 methacholine dose units was demonstrated (p < 0.018), this was not clinically significant; none of the 55 subjects converted a negative test to positive. We conclude that recent influenza vaccination is not a sufficient exclusionary criterion for methacholine challenge testing. Positive results in a patient recently vaccinated would still indicate asthma in the correct clinical setting.     

Region-specific localization of retinoic acid receptor-alpha expression in the rat epididymis

BACKGROUND: Nitric oxide (NO), a recognized cell messenger for activating soluble guanylate cyclase, is produced by the enzyme NO synthase in a wide variety of tissues, including vascular endothelium and the central nervous system. The authors previously reported the possible involvement of the NO pathway in the anesthetic state by showing that a specific NO synthase inhibitor, nitroG-L-arginine methyl ester (L-NAME), dose dependently and reversibly decreases the minimum alveolar concentration (MAC) for halothane anesthesia. The availability of a structurally distinct inhibitor selective for the neuronal isoform of NO synthase, 7-nitro indazole (7-NI), allowed for the possibility of dissociating the central nervous system effects of neuronal NO synthase inhibition from the cardiovascular effects of endothelial NO synthase inhibition. METHODS: The effect of two structurally distinct inhibitors of NO synthase, L-NAME and 7-NI, on the MAC of isoflurane was investigated in Sprague-Dawley rats while concurrently monitoring the animals' arterial blood pressure and heart rate. L-NAME (1 to 30 mg/kg given intravenously, dissolved in 0.9% saline) and 7-NI (20 to 1,000 mg/kg given intraperitoneally, dissolved in arachis oil) were administered after determining control MAC and 30 min before determining MAC in the presence of NO synthase inhibitor. RESULTS: L-NAME and 7-NI caused a dose-dependent decrease from isoflurane control MAC (maximal effect: 35.5 +/- 2.5% and 43.0 +/- 1.7%, respectively) with a ceiling effect observed for both NO synthase inhibitors (above 10 mg/kg and 120 mg/kg, respectively). L-NAME administration significantly increased systolic and diastolic blood pressures (maximal effect: 39.9 +/- 2.2% and 64.3 +/- 4.0%, respectively), which were not accompanied by any changes in heart rate. 7-NI administration resulted in no changes in blood pressure and a small but clinically insignificant decrease in heart rate. CONCLUSIONS: Inhibition of the NO synthase pathway decreased the MAC for isoflurane, which suggests that inhibition of the NO pathway decreases the level of consciousness and augments sedation, analgesia, and anesthesia. The MAC reduction by two structurally distinct NO synthase inhibitors supports that this is a specific effect on NO synthase. Furthermore, the action of the neuronal NO synthase inhibitor 7-NI supports an effect selective for neuronal NO synthase and also avoids the hypertensive response of generalized NO synthase inhibitors.