Coeliac haemodynamic effects of endothelin-1, endothelin-3, proendothelin-1 [1-38] and proendothelin-3 [1-41] in conscious rats.

1. Conscious, chronically-instrumented, Long Evans rats were given bolus doses of endothelin-1, endothelin-3 (both at 0.01 and 0.1 nmol kg-1), proendothelin-1 [1-38] and proendothelin-3 [1-41] (both 0.1 and 1 nmol kg-1) in order to compare their effects on coeliac haemodynamics, because it has been reported that, in conscious dogs, endothelin-1 has paradoxical, prolonged hyperaemic vasodilator effects in this vascular bed. Measurements were made also of mesenteric and hindquarters haemodynamics for comparison. In a separate experiment, endothelin-1 (0.1 nmol kg-1) was given before and 20 min after the onset of an infusion of mecamylamine (50 mumol kg h-1) to ensure that the responses measured were not confounded by rapid reflex changes in autonomic activity. 2. None of the peptides caused any increases in coeliac flow or any sustained rises in coeliac vascular conductance, although such changes were clear-cut in the hindquarters vascular bed following the higher dose of endothelin-1 and endothelin-3. In animals treated with mecamylamine the regional haemodynamic effects of the higher dose endothelin-1 were not different from those in animals with intact baroreflexes. 3. Although the lower dose of both endothelin-1 and endothelin-3 caused less marked coeliac, than mesenteric vasoconstriction, this difference was not apparent with the higher dose of the peptides, or with proendothelin-1 [1-38]. However, proendothelin-3 [1-41] had less marked coeliac and hindquarters vasoconstrictor effects than proendothelin-1 [1-38], in spite of both peptides causing similar changes in mesenteric haemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)     

p53 mutation and protein accumulation during multistage human esophageal carcinogenesis.

Preinvasive lesions of squamous cell carcinoma are well defined morphologically and provide a model for multistage carcinogenesis. Since alterations in the p53 tumor suppressor gene occur frequently in invasive esophageal squamous cell carcinoma, we examined a set of preinvasive lesions to investigate the timing of p53 mutation. Surgically resected tissues from nine patients with esophageal squamous cell carcinoma contained precursor lesions which had not yet invaded normal tissues. Immunohistochemistry showed high levels of p53 protein in both preinvasive lesions and invasive carcinomas in six cases; sequence analysis of all invasive tumors identified p53 missense mutations in two cases. Preinvasive lesions from both tumors with mutations plus one wild-type tumor were microdissected and sequenced. In one patient there were different mutations in the invasive carcinoma (codon 282, CGGarg > TGGtrp) and a preinvasive lesion (codon 272, GTGval > T/GTGleu/val). In a second case, an invasive carcinoma had a mutation in codon 175 (CGCarg > CAChis), and adjacent preinvasive lesions contained a wild-type sequence. A carcinoma and preinvasive lesion from the third case contained high levels of protein and a wild-type DNA sequence. Therefore, p53 mutation may precede invasion in esophageal carcinogenesis, and multifocal esophageal neoplasms may arise from independent clones of transformed cells. The timing of p53 protein accumulation is favorable for an intermediate biomarker in multistage esophageal carcinogenesis.     

The relationship between the Bayley Scales of Infant Development and preschool gross motor and cognitive performance

Early identification of disabilities enables early intervention by occupational therapists and other health professionals. Because the number of children who can be seen in therapy is limited, it is important to be able to identify those infants most likely to have deficits at a later age. Therefore, it is necessary to study and understand the relationship between infants' scores on early developmental assessments and later developmental outcomes. The purpose of this study was to determine the extent to which scores on the Bayley Scales of Infant Development (BSID) during the first 2 years of life are related to motor and cognitive performance at 4 1/2 years for a sample of children identified at birth as biologically high risk. This retrospective study involved 70 children who were evaluated at corrected ages of 4 months, 1 year, 2 years, and 4 1/2 years. The 4-month BSID Mental and Motor Scale scores did not relate significantly to later cognitive motor performance. In contrast, the 12-month BSID Mental Scale scores related significantly to preschool scores on both the motor and cognitive measures. However, the 24-month BSID Mental Scale scores related significantly only to scores on the preschool cognitive measures. Though significant, these correlation coefficients had small magnitudes. Thus, therapists should be cautious about using BSID testing at 4 months, 1 year, and 2 years when attempting to predict later preschool performance.     

L-arginine reverses the antinatriuretic effect of cyclosporin in renal transplant patients

BACKGROUND: Cyclosporin has been shown to facilitate renal vasoconstriction and to have an antinatriuretic effect. The existence of an interference of cyclosporin with the vasodilating properties of endothelium mediated by nitric oxide production could mediate these effects. On the other hand, the infusion of the nitric oxide precursor L-arginine has been shown to induce renal vasodilatation and to facilitate natriuresis in normal volunteers. We have investigated the renal effects of the administration of an infusion of L-arginine in renal transplant patients chronically treated with cyclosporin. To facilitate the analysis of the data the effects of the administration of a similar dose of cyclosporin on renal function during the infusion of a vehicle were also investigated during the administration of a vehicle of L-arginine. DESIGN: Ten male renal transplant patients, chronically treated with cyclosporin and with a stable renal function were studied during 2 consecutive days after the administration of the usual morning dose of cyclosporin. The first day they received an intravenous infusion of vehicle and the second the infusion of graded doses of L-arginine (50, 100, 150 mg/kg/h) during 3 consecutive h. RESULTS: The first day, after cyclosporin administration a significant fall (P < 0.01) was observed in natriuresis and kaliuresis in the absence of changes in renal plasma flow and glomerular filtration rate. After the administration of L-arginine significant (P < 0.01) increases of renal plasma flow, glomerular filtration rate, and natriuresis were seen. The increase in blood levels of cyclosporin after its administration did not differ between days 1 and 2. CONCLUSION: These results indicate that L-arginine facilitates renal vasodilatation and natriuresis in renal transplant patients. Furthermore, the observed increase in sodium excretion could indicate that L-arginine counteracts the antinatriuretic effect of cyclosporin.      

Tumour cell u-PA as a cause of fibrinolytic bleeding in metastatic disease

Tumour cells may express urokinase type plasminogen activator (u-PA). This may influence the invasive properties of the cells but has seldom been implicated in production of a systemic bleeding state. Two patients are described in whom severe bleeding occurred in association with disseminated malignancies. Thrombin generation was little disturbed and platelet numbers were insufficient to account for the bleeding. Florid plasmin generation was evident in the circulation and the fibrinolytic inhibitor tranexamic acid controlled the bleeding well. Free active u-PA was demonstrated in the circulation and u-PA antigen on the malignant cells which invaded the marrow of one of the patients. Tumour cell u-PA may occasionally be responsible for a bleeding state.     

Inhibition of the haemodynamic effects of angiotensin II in conscious rats by AT2-receptor antagonists given after the AT1-receptor antagonist, EXP 3174.

1. Conscious, Long Evans rats (n = 10), chronically instrumented for the measurement of regional haemodynamics, were studied on 3 consecutive experimental days to assess responses to angiotensin II (AII) (125 pmol kg-1, i.v.) and noradrenaline (1 nmol kg-1, i.v.) in the absence and presence of the AT2-receptor antagonist, PD 123319 (10 mg kg-1, i.v.) (day 1), the AT1-receptor antagonist, EXP 3174 (1 mg kg-1, i.v.) (day 2), and PD 123319 (10 mg kg-1, i.v.) given 24 h after EXP 3174 (day 3). 2. In naive rats (day 1), PD 123319 did not antagonize the haemodynamic effects of AII or noradrenaline. EXP 3174 (day 2) caused a marked, prolonged blockade of the haemodynamic effects of AII but not those of noradrenaline. Twenty four h after administration of EXP 3174 (day 3) there was still significant attenuation of the haemodynamic effects of AII. However, administration of PD 123319 at this time caused a further inhibition (lasting 1 h) of the effects of AII but not those of noradrenaline. 3. An identical 3 day protocol was used in a separate group of rats (n = 6) in which the AT2-receptor antagonist, PD 123177, was given instead of PD 123319, and the results were essentially the same, i.e., PD 123177 significantly attenuated the haemodynamic effects of AII but only when given 24 h after EXP 3174.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative study of roles of the lobus parolfactorius and intermediate medial hyperstriatum ventrale in memory formation in the chick brain.

Two discrete areas of the chick brain, the intermediate medial hyperstriatum ventrale (IMHV) and lobus parolfactorius (LPO), were found to have different functions during the formation of memory for a 1-trial peck-avoidance paradigm. Glutamate, ouabain, and emetine, known to disrupt short-, intermediate-, and long-term memory when injected into the IMHV, were injected into the cerebellum and LPO. All amnestic agents investigated produced amnesia when injected into the IMHV; only one of these agents produced amnesia when injected into the LPO, and none of the agents produced amnesia when injected into the cerebellum. The chick brain was also found to exhibit hemispheric asymmetries: The left IMHV and LPO were more sensitive to the amnestic agents than their corresponding right structure. From these data, hypotheses for the roles of these structures during memory are proposed.