Correlation between c-erbB2 expression, lymphovascular invasion and other biological and clinical prognostic factors and preoperative tumor markers in patients with early-stage and locally advanced breast cancer.

PURPOSE: To evaluate the correlation between c-erbB2 expression, lymphovascular invasion and other biological and clinical prognostic variables and preoperative CA 15-3 and CEA levels in patients with early-stage and locally advanced breast cancer. METHODS: Preoperative serum concentrations of CA 15- 3 and CEA were measured in 123 patients undergoing surgical treatment for stage I-III breast cancer and the association between these markers and clinical and biological variables were evaluated. RESULTS: With cut-off values of 45 U/ml (CA 15-3) and 2.5 ng/ml (CEA), the sensitivity for CA 15-3 and CEA was 10% and 24% and their mean values were 23 U/ml and 2.32 ng/ml, respectively. A significant correlation between preoperative levels of CA 15-3 and CEA was noticed (p=0.023). Preoperative CA 15-3 levels were significantly higher in patients with tumors > 5 cm (p<0.0001), with positive axillary lymph nodes (p=0.04), with increasing nodal burden (p= 0.025) and in patients with stage III disease (p=0.003). Tumor size >5 cm (p=0.002), increasing axillary nodal burden (p=0.02) and stage III disease (p<0.0001) were also significantly correlated with CEA values above the cut-off level. There were no correlations between CA 15-3 and CEA levels and other variables including c-erbB2 expression, age, grade, hormone receptor status, and lymphovascular invasion. CONCLUSION: Preoperative CA 15-3 and CEA levels are significantly correlated with tumor size, axillary nodal status and stage in patients with non-metastatic breast carcinoma. No correlation between preoperative values of CA15-3/CEA and c-erbB2 status, lymphovascular invasion and other prognostic factors was detected.

Acute laryngeal and bronchial obstruction after CS (o-chlorobenzylidenemalononitrile) gas inhalation.

CS gas (o-chlorobenzylidenemalononitrile) is one of the most commonly used riot agents. It can create excessive tearing, conjunctivitis, uncontrolled blinking (blepharospasm) and a sensation of burning and pain at initial exposure. Pulmonary edema (ARDS) and/or diffuse airway lesions on human would be lethal after CS inhalation. We report a case with acute laryngeal and bronchial obstruction due to vocal cord edema and extensive crusting at glottic level, trachea and bronchi. The CS gas was sprayed in a 6 x 6 m(2) closed room, and she was exposed to increased concentration of the gas for 10 s. Surprisingly, her initial symptoms were raised 21 days after CS spray exposure.

Secondhand tobacco smoke impairs neurogenic and endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle: improvement with chronic oral administration of L-arginine.

The first goal of this study was to examine the effect of secondhand smoking on neurogenic, endothelium- and cGMP-dependent relaxant responses of rabbit corpus cavernosum smooth muscle. Our second goal was to determine whether such an effect can be prevented by oral administration of L-arginine. Male New Zealand rabbits were divided into control, chronic passive cigarette smoking and L-arginine treatment groups. Relaxant or contractile responses in isolated corpus cavernosum smooth muscle strips were determined by using in vitro muscle technique. There was no significant difference in the relaxant response of the strips to papaverine, sodium nitroprusside and contractile response to KCl among the groups. Relaxant responses to acetylcholine and electrical field stimulation and contractile response to phenylephrine were significantly decreased in the strips of the smoking group than that of the control group. The impaired relaxations of strips were markedly improved by treatment of L-arginine, but the contractile responses to phenylephrine were not affected. These data indicate that secondhand smoking may impair both neurogenic and endothelium-dependent relaxation of corpus cavernosum smooth muscle, and may contribute to the etiology of impotence. Chronic dietary supplementation with L-arginine offsets the impairment of neurogenic and endothelial relaxation. Therefore, we suggest that secondhand smoking exposure to cigarette produces selective impairment of neurogenic and endothelium-dependent relaxation of corpus cavernosum smooth muscle via a mechanism related to the decreased production and/or availability of nitric oxide.

Effect of valsartan versus lisinopril on peritoneal sclerosis in rats.

BACKGROUND: Peritoneal sclerosis (PS) is one of the most serious causes of failure in long-term peritoneal dialysis. Angiotensin II is known to promote fibrosis and inflammation in various tissues. We previously showed that ACE inhibitors (ACEIs) have beneficial effects on hypertonic PD solutions (3.86% PD) induced peritoneal alterations. The aim of this study is to compare the effects of an ACEI and a receptor blocker on peritoneal alterations induced by hypertonic PD solutions in rats. METHODS: Forty-three non-uremic rats were divided into four groups: group I (Sham) rats received no treatment (n=11), group II received hypertonic (3.86%, 10 ml/day) PD solution (n = 10) and groups III and IV received hypertonic PD solution (10 ml/day) plus 640 mg/L valsartan (n=11) and 100 mg/L lisinopril in drinking water (n = 11). After four weeks, a one-hour peritoneal equilibration test (PET) was performed with 3.86% PD solution. Dialysate-to-plasma urea ratio (D/P urea), glucose reabsorption (D 1 /D 0 glucose), ultrafiltration volume (UF), dialysate protein, TGFbeta 1 and VEGF levels were determined. RESULTS: Administration of valsartan or lisinopril resulted in preserved UF (8+/-0.8 and 6.7+/-0.7 vs 4.9+/-0.8 mL), D1/D0 glucose (0.69+/-0.05 and 0.62+/-0.05 vs 0.56+/-0.04) and peritoneal thickness (19.4+/-2.9 and 28.5+/-5.2 vs 53+/-3 microm), respectively. Both higher level of TGF beta 1 (206+/-40 vs 474+/-120 pg/mL, p<0.05), and VEGF in dialysate effluent (4+/-0.4 vs 7.9+/-3 pg/mL, p>0.05), was determined in the dextrose group. Both cytokines are partially inhibited by valsartan or lisinopril (p >0.05) CONCLUSION: Exposure to hypertonic glucose solution resulted in alterations in peritoneal transport manifested by a rapid dissipation of the glucose gradient and resultant impaired UF response. Administration of valsartan or lisinopril led to attenuation of these alterations. We suggest that the equal protection of the peritoneal membrane from the effects of hypertonic glucose was achieved by receptor blockers and ACE inhibitors.

Neurobiology and treatment of anxiety: signal transduction and neural plasticity.

The stress-dependence and chronic nature of anxiety disorders along with the anxiolytic effectiveness of antidepressant drugs suggests that neuronal plasticity may play a role in the pathophysiology of anxiety. Intracellular signaling pathways are known in many systems to be critical links in the cascades from surface signals to the molecular alterations that result in functional plasticity. Chronic antidepressant treatments can regulate intracellular signaling pathways and can induce molecular, cellular, and structural changes over time. These changes may be important to the anxiolytic effectiveness of these drugs. In addition, the signaling proteins implicated in the actions of chronic antidepressant action, such as cAMP response element binding protein (CREB), have also been implicated in conditioned fear and in anxiety. The cellular mechanisms underlying conditioned fear indicate roles for additional signaling pathways; however, less is known about such mechanisms in anxiety. The challenge to identify intracellular signaling pathways and related molecular and structural changes that are critical to the etiology and treatment of anxiety will further establish the importance of mechanisms of neuronal plasticity in functional outcome and improve treatment strategies.

Inducible, brain region-specific expression of a dominant negative mutant of c-Jun in transgenic mice decreases sensitivity to cocaine.

Administration of cocaine induces the Fos family of transcription factors in the striatum, including the nucleus accumbens (NAc), a brain region important for the rewarding effects of addictive drugs. Several Fos proteins are induced acutely by cocaine, with stable isoforms of DeltaFosB predominating after chronic drug administration. However, it has been difficult to study the functional consequences of these Fos responses in vivo. Fos proteins heterodimerize with members of the Jun family to form active AP-1 transcription factor complexes. In the present study, we took advantage of this property and generated transgenic mice, using the tetracycline gene regulation system, that support the inducible, brain region-specific expression of a dominant negative mutant form of c-Jun (Deltac-Jun), which can antagonize the actions of Fos proteins. Expression of Deltac-Jun in the striatum and certain other brain regions of adult mice decreases their development of cocaine-induced conditioned place preference, suggesting reduced sensitivity to the rewarding effects of cocaine. In contrast, Deltac-Jun expression had no effect on cocaine-induced locomotor activity or sensitization. However, expression of Deltac-Jun in adult mice blocked the ability of chronic cocaine administration to induce three known targets for AP-1 in the NAc: the AMPA glutamate receptor subunit GluR2, the cyclin-dependent protein kinase Cdk5, and the transcription factor nuclear factor-kappaB (NFkappaB), without affecting several other proteins examined for comparison. Taken together, these results provide further support for an important role of AP-1-mediated transcription in some of the behavioral and molecular mechanisms underlying cocaine addiction.

Age and gender dependent alterations in the activities of glutathione related enzymes in healthy subjects.

OBJECTIVES: Oxidative stress as a result of increased free radical production is implicated in the pathogenesis of several diseases. Specific antioxidant enzymes have a crucial role in the prevention of these deleterious effects. Since the activities of these enzymes differ significantly in different populations and seem to be affected by various environmental factors, in this study we aimed to determine the reference values of glutathione related antioxidant enzyme activities in the erythrocytes of healthy subjects and to investigate the possible variations as a function of age and gender in a healthy Turkish Mediterranean population. DESIGN AND METHODS: 130 healthy subjects (12-90 yr, 82 females, 48 males) were divided into six different age groups. Erythrocyte glutathione peroxidase (GSH-PX), glutathione reductase (GR) and glutathione-s-transferase (GST) activities were measured on a Hitachi 704 autoanalyser by the modification of previously described manual UV spectrophotometric methods. RESULTS: No significant differences were observed in erythrocyte GSH-PX, GR and GST activities between different age groups. Overall, GST activities were significantly higher in females compared with males (8.08 +/- 1.39, 6.88 +/- 1.51 U/g Hb respectively, mean +/- SD, p < 0.001). A significant positive correlation between GSH-PX and GR activities was observed (r = 0.49, p < 0.001). CONCLUSION: The results of this study suggested that the activities of GSH-PX, GR and GST did not depend. GST activities overall were higher in females. The reference values that we obtained were different than the previous reports. This situation implies that each population should determine its own reference values and should investigate the influence of environmental factors and life style habits on the activities of these enzymes that constitute a major part of the antioxidant defense system in the human organism.

Fear conditioning and latent inhibition in mice lacking the high affinity subclass of nicotinic acetylcholine receptors in the brain.

Nicotine can enhance performance in several tests of cognition but the specific nicotinic receptor subtypes mediating these effects are largely unknown. Knock out mice lacking the beta2 subunit of the nicotinic receptor were evaluated in fear conditioning and latent inhibition tasks to begin to determine which receptor subtypes mediate the cognitive effects of nicotine. Young (2-4 months) knock out and wild type mice did not differ in either contextual or tone-conditioned fear, but aged (9-20 months) knock out males were impaired in freezing to both context and tone compared to aged wild type males. No differences in fear conditioning were observed between aged knock out and wild type females. Latent inhibition of fear to a pre-exposed tone, as measured by behavioral freezing, was also assessed. Both knock out and wild type mice displayed similar levels of latent inhibition, although overall levels of freezing were lower in knock out mice. These results support a previous study showing spatial learning deficits in aged beta2 subunit knock out mice [EMBO J. 18 (1999) 1235] and suggest that performance of other cognitive tasks may not be influenced by absence of beta2 subunit-containing receptors.

Effects of defibrotide on aorta and brain malondialdehyde and antioxidants in cholesterol-induced atherosclerotic rabbits.

The effects of a high-cholesterol diet in the presence and absence of defibrotide, a single-stranded polydeoxyribonucleotide compound, on the lipid peroxidation product malondialdehyde, endogenous antioxidant enzymes catalase, glutathione peroxidase, and the antioxidant thiol compound GSH were investigated. Forty male New Zeland white rabbits were divided into four groups each consisting of 10 rabbits. Group I received a regular rabbit chow diet and group II 1% cholesterol plus regular chow, group III was given defibrotide (60 mg/kg per day p.o. in water) and was fed with regular chow, and group IV received defibrotide plus 1% cholesterol for 9 weeks. Blood cholesterol and malondialdehyde, catalase, glutathione peroxidase, and GSH were determined before starting the experimental diet regimen (basal). After 9 weeks, the same parameters were determined in blood, aorta, and brain tissues (end -experiment). Aortic tissue was examined under a light microscope for morphological alterations indicative of atherosclerosis. The increase in serum total cholesterol was greater in group II than group IV. Plasma malondialdehyde in group II was higher than in group III. Brain malondialdehyde in group II was higher than all other groups, and aortic malondialdehyde in this group was higher than group I and III. Serum catalase activity decreased in group II and increased in group III, compared with basal values. Brain catalase activity in group I was higher than group II, and aorta catalase in group IV was higher than in group I and III. Blood glutathione peroxidase activity in group III and IV was higher than basal. GSH concentrations decreased significantly in the cholesterol-fed groups (group II and IV). Histological alterations in the cholesterol-fed groups were more pronounced in group II. The increased levels of malondialdehyde in plasma, aorta, and brain tissue of group II suggest a role of oxygen free radicals in the pathogenesis of cholesterol-induced atherosclerosis. The higher malondialdehyde values in the brain tissues of animals in group II compared with group IV suggest a protective role of defibrotide in the brain against lipid peroxidation in the oxidant stress of cholesterol-induced atherosclerosis. Increased catalase activities in the blood and aortic tissues and increased glutathione peroxidase activities in the blood of rabbits receiving defibrotide suggest an induction of these antioxidant enzyme activities by defibrotide. These results imply that anti-atherosclerotic, anti-ischemic effects of this drug may be due to the beneficial effects on the oxidant-antioxidant balance of various tissues.

Distinct but overlapping populations of commissural and GABAergic neurons in the dorsal nucleus of the little skate, Raja erinacea.

In the little skate, Raja erinacea, the electrosensory primary afferents are responsive to electrical potentials created during the animal's own ventilation, while second-order electrosensory cells in the dorsal nucleus of the medulla suppress the responses to ventilatory potentials but retain their extreme sensitivity to important environmental electric signals. Previous electrophysiological studies indicate a role for a commissural pathway between the bilateral dorsal nuclei in ventilatory noise suppression. In the present study, retrograde tracers were used to label dorsal nucleus commissural cells. Large round or triangular and thin elongate commissural cells occur in the central zone of the dorsal nucleus where the primary afferent fibers terminate. Elongate commissural cells also occur in the peripheral zone which is the cell body area of the major efferents of the dorsal nucleus. Immunohistochemical studies indicate that stellate cells of the molecular layer and round or triangular cells of the central zone comprise the GABA-immunoreactive cell groups of the dorsal nucleus. A subpopulation of the round commissural cells in the central zone are GABA-immunoreactive and may be candidates for mediators of common-mode noise rejection in the dorsal nucleus of skates. The non-GABAergic commissural cells may mediate crossed inhibition through an inhibitory transmitter other than GABA or may supply crossed excitation to the dorsal nucleus.

Short-latency interneurons in the dorsal nucleus of the little skate, Raja erinacea.

The elasmobranch electrosensory system is the most thoroughly understood of the non-teleost electrosensory systems and is useful for studying central nervous system mechanisms for the separation of behaviorally relevant signals from self-generated noise. In the little skate, Raja erinacea, the electrosensory primary afferents are responsive to electrical potentials created during the animal's own ventilation, while second-order neurons in the dorsal nucleus of the medulla suppress responses to ventilatory potentials (self-generated noise) but retain their extreme sensitivity to electric signals in the environment. The selective suppression of ventilatory noise in second-order cells is due in part to the fact that ventilatory potentials stimulate all receptors equally and simultaneously. The neuronal circuitry mediating rejection of such 'common mode' signals in the dorsal nucleus likely includes inhibitory interneurons. This study describes physiological and anatomical characteristics of a group of dorsal nucleus interneurons that are distinguished from previously described interneurons by their shorter orthodromic activation latencies and higher spontaneous firing rates. The interneurons show sustained responses to an external dipole stimulus and respond well during simultaneous activation of all afferents by a 'common mode' stimulus. Intracellular labeling indicates that the short-latency interneurons are located in the central and peripheral zones of the dorsal nucleus and the extent of their labeled processes is limited to the projection area of afferents from a single ampullary cluster. These features are consistent with a hypothesized role for these interneurons in inhibiting second-order cells, including inhibition which contributes to common mode rejection.

A role for GABAergic inhibition in electrosensory processing and common mode rejection in the dorsal nucleus of the little skate, Raja erinacea.

The electrosensory primary afferents in elasmobranchs are responsive to electric potentials created by the animal's own ventilation, while the second-order neurons (AENs) which receive this afferent input in the medulla suppress responses to ventilatory potentials but retain their extreme sensitivity to electric signals in the environment. Ventilatory potentials are common mode signals in elasmobranchs and a common mode rejection mechanism is one way the AENs suppress ventilatory noise. By pressure injecting the GABA-A receptor antagonist SR95531 while extracellularly recording from AENs, we tested the hypothesis that the subtractive circuitry that selectively reduces common mode signals in AENs utilizes GABA, and that a GABAergic component of the dorsal nucleus commissural pathway mediates crossed inhibition of AENs. Local application of SR95531 increased the spontaneous activity and the responsiveness of AENs to electrosensory stimuli. AEN responses to a common mode stimulus were selectively increased compared to responses to a localized stimulus due to SR95531 application. Contralateral inhibition of AENs was blocked by SR95531, indicating that GABAergic commissural cells may inhibit AENs when the contralateral side of the body is stimulated, as with common mode stimulation. We conclude that GABAergic inhibition contributes significantly to the shaping of AEN responses including common mode rejection.