Toe temperature versus transcutaneous oxygen tension monitoring during acute circulatory failure

Measurements of toe temperature and transcutaneous PO₂ (P_tcO₂) have been both suggested for non-invasive assessment of peripheral blood flow in acute circulatory failure. The underlying principle of the two methods is that cutaneous vasoconstriction occurs early when tissue perfusion is altered. In 15 patients, we compared the two measurements during cardiogenic shock (27 measurements) or septic shock (29 measurements). Toe-ambiant temperature gradient and P_tcO₂ correlated well together (r=0.66, p(0.001) especially in hyperkinetic septic shock (r=0.79, p(0.001). In cardiogenic shock, toe-ambiant temperature correlated well with cardiac index (r=0.63), stroke index (r=0.64) and oxygen transport (r=0.65), and these correlations were stronger than for P_tcO₂. In septic shock, both techniques were poor indicators of blood flow indexes but P_tcO₂ rather correlated with arterial pressure (r=0.66) and left ventricular work (r=0.66). Trend evaluation of data revealed in cardiogenic shock that the increase in toe temperature usually preceded the increase in P_tcO₂. Since measurement of P_tcO₂ is technically more complicated, correlates less well with standard hemodynamic parameters and later reflects cardiovascular improvement, it has no advantage over measurement of toe temperature in circulatory shock. In cardiogenic shock, measurements of toe temperature can reliably track cardiac output changes. In septic states, however, non-invasive assessment of skin perfusion is of limited interest.     

Evidence for nitric oxide participation in down-regulation of CYP2B1/2 gene expression at the pretranslational level

Septic or inflammatory stimuli suppress drug metabolism by cytochrome P-450 in the liver, presumably at the pretranslational level. We have shown previously that nitric oxide is responsible at least in part for the inhibition by bacterial lipopolysaccharide of phenobarbital-induced CYP2B1/2 activity in vivo. This was attributed to the interaction of nitric oxide with heme in the active-center of cytochrome P450, leading to enzyme inactivation. Here, we report of nitric oxide with heme in the active-center of cytochrome P450, leading to enzyme inactivation. Here, we report that endogeneous nitric oxide also contributes to LPS-induced suppression of CYP2B1/2 in vivo by down-regulating the expression of CYP2B1/2 protein and mRNA.     

Immunohistochemical Study of Colorectal Polyps with Antibodies against CEA,CA19-9, CA125, CA15-3 (DF3), PCNA and p53

Abstract: We analyzed the expression of CEA, CA19-9, CA125, CA15-3 (DF3), PCNA and p53 immunohistochemically in 14 tissue specimens of mucosal cancers in adenoma, seven tubulovillous adenoma specimens, and 16 tubular adenoma specimens. The rates of positive staining for mucosal cancer in adenoma, tubulovillous adenoma and tubular adenoma specimens, respectively, were: for CEA: 100%, 85.7% and 75%; for CA19-9: 71.4%, 71.4% and 56.2%; for CA125:0%, 0% and 0%;for CA15-3 (DF3): 64.3 %, 0% and 0 %; for PCNA: 100%, 88.9% and 56.2%; and for p53: 35.7%, 0% and 0% . The results suggest that the expressions of CEA, CA19-9, CA15-3 (DF3), PCNA and p53 are related to colorectal tumorigenesis. None of the specimens studied showed staining for CA125, suggesting that CA125 is not involved in the early stages of colorectal carcinogenesis. There was no significant difference in the rates of positive staining for CEA and CA19-9 among mucosal cancer in adenoma, tubular adenoma and tubulovillous adenoma specimens. However, the rates of positive staining for PCNA and p53 were significantly higher in mucosal cancer in adenoma specimens than for tubular adenoma specimens (p<0.05), and the rate of CA15-3 (DF3) positive staining was significantly higher for mucosal cancer in adenoma than for tubulovillous adenoma (p<0.01) and tubular adenoma (p< 0.001) specimens. Therefore, the CA15-3 (DF3) antigen is an immunohistochemical marker for colorectal carcinomas. The present results suggest that CA15-3 (DF3), PCNA and p53 play important roles in the genesis of colorectal adenomas.     

Synthesis and Evaluation of Azole-Substituted Tetrahydronaphthalenes as Inhibitors of P450 arom,P450 17, and P450 TxA2

In search of potential drugs for the treatment of estrogen- and androgen-dependent cancer as well as the prophylaxis of metastases, tetralones, tetralins, and dihydronaphthalenes bearing a OCH₃ substituent at the benzene nucleus and an imidazol-4-yl, imidazol-1-yl, or 1,2,4-triazol-1-yl substituent in 2-position were synthesized with and without C₁-spacer between the rings (compounds 2 – 26 ). The compounds were tested in vitro for inhibition of the three target enzymes P450 arom (human placental microsomes), P450 17 (rat testicular microsomes), and P450 TxA₂ (citrated human whole blood). To examine selectivity, some compounds were further tested in vitro for inhibition of P450 18 (bovine adrenal mitochondria), P450 see (bovine adrenal mitochondria) and corticoid formation (aldosterone, corticosterone; ACTH stimulated rat adrenal tissue). In vivo, selected compounds were examined in Sprague Dawley rats regarding P450 TxA₂ inhibition, reduction of plasma testosterone concentration, antiuterotrophic activity (inhibition of the uterotrophic activity of androstenedione), reduction of plasma estradiol concentration (pregnant mares' serum gonadotropin-primed rats), and mammary tumor inhibiting activity (dimethylbenzanthracene-induced tumor; pre- and postmenopausal model). In the series of imidazol-4-yl compounds, which represent a novelty in the field of azole inhibitors of steroidogenic P450 enzymes, strong inhibitors of P450 arom and/or P450 17 were found: 7-OCH₃-2-(imidazol-4-ylmethylene)-1-tetralone ( 4 ) and 7-OCH₃-2-(imidazol-4-ylmethyl)-tetralin ( 12 ) are among the most potent inhibitors of P450 arom in vitro known so far. Compound 4 is a selective inhibitor, whereas 12 shows in addition strong inhibition of P450 17. In contrast to 12 , the 6-OCH₃ derivative (compound 11 ) is a selective inhibitor of P450 17, being 50 times more potent than ketoconazole. Some imidazol-1-yl compounds show a marked inhibition of P450 TxA₂: 2-(imidazol-1-ylmethyl)-1-tetralone ( 13 ) is a selective inhibitor of P450 TxA₂, whereas 7-OCH₃-2-(imidazol-1-ylmethyl)-tetralin ( 17 ) as well as 2-(imidazol-1-ylmethyl)-tetralin ( 16 ) and 7-OCH₃-2-imidazol-1-yl-3,4-dihydronaphthalene ( 25 ) additionally show strong inhibition of P450 arom and P450 17. Regarding the other steroidogenic P450 enzymes as well as corticosterone formation, the compounds show only little inhibitory activity. Aldosterone formation, however, is inhibited at low concentrations. Nevertheless, 4 and 12 are more selective, i.e. inhibit aldosterone synthesis less than the well known inhibitor of P450 arom fadrozole. The compounds show activity in the aforementioned in vivo tests.     

Nicotine interactions with dopamine agonists: Effects on working memory function

Nicotine has been found to improve memory performance in a variety of tests including the radial-arm maze. Nicotine may have effects mediated by promoting the release of dopamine. The present study was conducted to determine the interactions of nicotine with D₁ and D₂ agonists. Rats were acutely administered nicotine, the D₁ agonist SKF 38393, and D₂/D₃ agonist quinpirole, and nicotine together with each of these agonists. Nicotine significantly improved choice accuracy in the radial-arm maze. The D₁ agonist SKF 38393 significantly impaired choice accuracy. Nicotine was effective in reversing this effect. The D₂/D₃ agonist quinpirole showed a trend toward potentiating the improvement in choice accuracy caused by 0.2 mg/kg (0.43 μmol/kg) of nicotine. These data show that, as with the nicotinic antagonist mecamylamine, there are significant interactions of dopamine systems with nicotine effects. © 1994 Wiley-Liss, Inc.     

Biochemical evidence for the involvement of central serotonergic neurotransmission in the action of the antidepressant drug Medifoxamine

Medifoxamine, an antidepressant agent which has an original chemical structure, has been shown through in vitro studies, utilising radioligand binding in tissue homogenates, to bind with moderately high affinity to 5-HT_1c and 5-HT₂ receptor subtypes and to 5-HT uptake sites (IC₅₀ 950, 980, and 1,500 nM, respectively). It has been shown to bind in vivo to rat brain 5-HT₂ receptors after acute treatment with high dose (50 mg/kg, i.e., 133.9 μmol/kg). After 14 days continuous treatment with low dose (20 mg/kg, 53.6 μmol/kg), a decrease in the capacity of [³H]-5-HT uptake and a dose-dependent down-regulation of 5-HT₂ receptors in rat cerebral cortex were observed. These results indicate that medifoxamine, which has been shown previously to act through dopaminergic systems, interacts also with central serotonergic neurotransmission and particularly with the 5-HT₂ receptors, which could contribute to its antidepressant effect.     

CHANGES IN PREJUNCTIONAL POTENCY OF B-HT 933 DURING AGING IN THE RAT VAS DEFERENS

1. Age-related changes in prejunctional alpha 2-adrenoceptors were examined in the rat vas deferens using pharmacological techniques. 2. B-HT 933 (1 x 10(-8) - 1 x 10(-6) mol/L) caused a concentration-dependent inhibition of isometric contractions (tetrodotoxin-sensitive) induced by stimulation with single field-stimulus pulses, in both the epididymal and prostatic regions of rat vas deferens. The concentration-response curve to B-HT 933 was shifted to the right with age in the prostatic regions of the vas deferens. 3. In high concentrations (10(-6) - 3 x 10(-4) mol/L), B-HT 933 caused concentration-dependent enhancement of the contractile response to stimulation and evoked spontaneous contractile activity. No significant difference in this postjunctional activity occurred with age in either the prostatic or epididymal regions of the vas deferens. 4. Schild analysis revealed no significant differences in pA2 values for the antagonisms of the prejunctional inhibitory effect of B-HT 933 by rauwolscine in either the prostatic or epididymal regions of vas deferens between young and old rats. 5. These results could be interpreted as a decrease in alpha 2-adrenoceptor number with age. The more marked decrease in the prejunctional inhibitor potency of B-HT 933 in prostatic regions of vas deferens with aging may be due to a smaller receptor reserve in this region of the vas deferens.     

Interleukin-2, its soluble receptor,and soluble T8 antigen in acute ischemic stroke

The treatment of neoplasia with interleukin-2 (IL-2) can be complicated by neurological deficits resembling transient Ischemic attack and stroke. We investigated whether interleukin-2 contributes to the natural course of cerebrovascular ischemia and particularly to the pathogenesis of infection-associated stroke. Plasma levels of interleukin-2 were below the level of detectability in almost all measurements. Patients with and without previous infection (n = 11, 805 ±445 U/ml vs n = 19, 824 ± 501 U/ml) did not have significantly higher levels of soluble interleukin-2 receptors than control subjects with (n = 14, 667 ± 229 U/ml) or without vascular risk factors (n = 17, 567 ± 176 U/ml). Receptor levels increased in patients during the first week after stroke (n = 15, 1157 ± 1013, p < 0.02). Levels of soluble T8 antigen (sT8) were higher in patients (n – 26, 320 ± 112 U/ml) than in healthy control subjects (n = 15, 246 ± 92 U/ml; p < 0.05) and sT8 levels increased during the first week after stroke (p < 0.05). These results reflect an immunological response to the cerebral infarct; they do not indicate a general role of the IL-2 system in the pathogenesis of ischemic stroke with or without previous infection.     

Evidence for the presence of substance P-like immunoreactivity in the human cerebellum

Preliminary results on the localization of substance P-like immunoreactivity in the human cerebellum are presented. Cerebella from newborn and adult subjects were examined. While only sporadic positive fibres were detected in the adult tissue, the immunoreactive material appeared more abundant in the cerebella from newborn subjects. Varicose and non-varicose fibres and dot-like nerve terminals were present with different density in various regions. The paucity of immunoreactive perikarya suggests that most of the cerebellar substance P-like immunoreactive material has an extrinsic origin.