INTERACTION BETWEEN EPIDERMAL GROWTH FACTOR AND ARGININE VASOPRESSIN IN RENAL MEDULLARY MEMBRANES

1. Epidermal growth factor is a potent mitogen that causes natriuresis, diuresis and inhibition of arginine vasopressin-induced water reabsorption. 2. The aim of this study was to determine any interaction between epidermal growth factor and the V1 (vascular) and/or V2 (antidiuretic) arginine vasopressin receptor subtypes. 3. Radioligand binding displacement assays demonstrated that although arginine vasopressin related peptides displaced both radioligands from renal medullary membranes at low concentrations epidermal growth factor displaced neither. 4. Arginine vasopressin V2 receptor second messenger cyclic adenosine monophosphate (CAMP) production was inhibited by epidermal growth factor (IC₅₀ 2 ± 10^?7 mol/L) as was sodium fluoride cAMP production but only at much higher concentrations. 5. Therefore the diuretic effect of epidermal growth factor is not via direct antagonism of arginine vasopressin receptors but seems mediated via inhibition of the V2 second messenger system.     

Effects of mifepristone on rabbit intraocular pressure in the presence and absence of dexamethasone

Topical dexamethasone was used to elevate rabbit intraocular pressure in order to study the interaction with a steroid antagonist, mifepristone. Dexamethasone did not cause a consistently significant increase in intraocular pressure. Animals treated with mifepristone followed by dexamethasone showed no apparent increase in intraocular pressure after dexamethasone, indeed mifepristone caused a lower intraocular pressure than seen in other groups whether in the presence or absence of dexamethasone. Reductions of intraocular pressure when mifepristone was given after 14 days of dexamethasone administration were not found. No conclusion can be reached regarding any dexamethasone antagonism by mifepristone, except that intraocular pressure tended to be lower even in the presence of dexamethasone.     

The value of CT in determining potential instability of simple wedge-compression fractures of the lumbar spine.

PURPOSETo determine whether plain films alone are sufficient in the evaluation of stability of simple wedge-compression fractures of the lumbar spine.METHODSPlain films and CT scans of 53 consecutive patients seen during a 2-year period with lumbar spine fractures were retrospectively reviewed. Six readers blinded to the CT diagnosis independently read each patient''s plain films. Plain-film findings were scored on a five-point graded response scale using criteria proposed by Gehweiler and Daffner. In addition, a fracture was considered to be possibly unstable if there was involvement of more than one vertebral level or greater than 50% loss of anterior vertebral body height. CT findings represented the standard for comparison. CT scans were independently evaluated by three additional readers. Two-column involvement, middle-column involvement alone but with retropulsion, multiple-level involvement, or greater than 50% loss of vertebral height indicated potential instability.RESULTSFor 14 stable and 39 potentially unstable lumbar spine fractures, the pooled (mean) plain-film negative predictive value for detection of potentially unstable fractures was 0.62 (95% confidence interval, 0.53 to 0.70), with a sensitivity of 0.83 (95%, confidence interval; 0.78 to 0.87), and specificity of 0.80 (95% confidence interval, 0.70 to 0.87).CONCLUSIONPlain films are not adequate for determining stability of lumbar spine fractures.     

Effects of methyl isocyanate on rat muscle cells in culture.

Since the Bhopal disaster, in which the causal agent was methyl isocyanate (MIC), exposed people have complained of various disorders including neuromuscular dysfunction. In an attempt to gain some information about the response of muscle tissue to MIC its effects were investigated in cells in culture isolated from muscle of 2 day old rats. After treatment with a range of MIC concentrations (0.025-0.5 microliter/5 ml culture) the total number of nuclei of the two main cell types (fibroblasts and myoblasts) and the number of nuclei in muscle fibres (myotubes) were recorded. At lower doses which had little effect on the total number of nuclei, the formation of muscle fibres--that is, fusion of muscle cells--was prevented as the proportion of nuclei in myotubes was decreased. At higher doses both cell types were killed. This would suggest either an effect on muscle differentiation or a selective toxicity towards myoblasts. The observations were supported by light and electron microscopy.     

Factors involved in the anti-cancer activity of the investigational agents LM985 (flavone acetic acid ester) and LM975 (flavone acetic acid)

LM985 has been shown previously to hydrolyse to flavone acetic acid (LM975) in mouse plasma and to produce significant anti-tumour effects in transplantable mouse colon tumours (MAC). It has undergone Phase I clinical trials and dose limiting toxicity was acute reversible hypotension. Substantially higher doses of LM975 can be given clinically without dose limiting toxicity. We have investigated the activity of LM975 against a panel of MAC tumours and also the in vitro cytotoxicity of both LM985 and LM975 in two cell lines derived from MAC tumours. LM985 is considerably more cytotoxic than LM975 in vitro but increased length of exposure to LM975 results in improved activity. Single in vivo injection of LM975 showed no activity against the ascitic tumour MAC 15A, moderate activity against the s.c. poorly differentiated tumour MAC 13 and produced a significant growth delay in the well differentiated MAC 26. These latter responses were considerably enhanced by repeated injection 7 days later. Pharmacokinetic studies in mice following i.p. injection of LM985 demonstrated rapid degradation of LM985 to LM975 in the peritoneum. Length of exposure as well as drug concentration appear important factors in determining anti-tumour responses.     

Alpha 2U-globulin: measurement in rat kidney and relationship to hyaline droplets

The concentration of renal alpha 2U-globulin increased in a dose-dependent manner in adult male but not female rats which received a single dose of 2,2,4-trimethylpentane (TMP). After administration of a single dose of 12 mmol TMP/kg to adult male rats, the renal concentration of alpha 2U-globulin reached a peak at 48 hours and returned to near background level after 7 days. These changes in renal alpha 2U-globulin concentration were closely paralleled by changes in renal hyaline droplet formation. Renal alpha 2U-globulin and hyaline droplets were absent in normal pre-puberty male rats, and neither could be stimulated by a single dose of TMP. alpha 2U-Globulin was localised in the renal cortex of adult male rats, in particular the S2 segment of the proximal tubule. A greater staining intensity due to alpha 2U-globulin was seen in the S2 and adjacent segments after a single dose of TMP. A strong association is suggested between the presence of renal hyaline droplets and the occurrence of alpha 2U-globulin.     

Temporal variation in triazolam pharmacokinetics and pharmacodynamics after oral administration

The effect of time of day of drug administration on triazolam pharmacokinetics was studied in ten healthy men. In a randomized, two-way, crossover investigation, each subject received one 0.5 mg triazolam tablet either in the morning (7 AM) or evening (10 PM). Blood samples were obtained immediately before dosing and at selected times up to 12 hours after dosing. Triazolam plasma concentrations were determined by gas chromatography with electron capture detection. Psychomotor performance tests, including digit symbol substitution, card sorting by suits, and card sorting by fours, were administered, and the subjects' sedation was rated before drug and at two, ten, and 12 hours after drug administration. In addition, anterograde amnesia was assessed by showing objects to subjects two hours after dosing and testing aided and unaided recall at ten hours following administration. Triazolam's apparent elimination half-life after evening administration was significantly longer than after daytime ingestion (3.77 hr vs. 2.94 hr, P less than .05). There was no difference between times of dosing in total oral clearance or apparent volume of distribution. The absorption of triazolam was slower after evening administration, with an absorption half-life of 21.9 vs 13.3 minutes after daytime dosing. Performance decrements were significantly greater two hours after dosing in evening than in the daytime, but anterograde amnesia was more pronounced after daytime dosing. There was no effect on psychomotor performance at ten or 12 hours after administration in daytime or evening. These results indicate temporal variation in triazolam absorption and elimination.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of simplifying choice tasks on estimates of taste heterogeneity in stated-choice surveys

Researchers usually employ orthogonal arrays or D-optimal designs with little or no attribute overlap in stated-choice surveys. The challenge is to balance statistical efficiency and respondent burden to minimize the overall error in the survey responses. This study examined whether simplifying the choice task, by using a design with more overlap, provides advantages over standard minimum-overlap methods. We administered two designs for eliciting HIV test preferences to split samples. Surveys were undertaken at four HIV testing locations in San Francisco, California. Personal characteristics had different effects on willingness to pay for the two treatments, and gains in statistical efficiency in the minimal-overlap version more than compensated for possible imprecision from increased measurement error.