Trinitrotoluene (TNT) and related compounds were tested for induction of mutation in the CHO-hprt mutation assay. The parent compound, TNT, was consistently found to be mutagenic at concentrations above 40 microg ml(-1), whether or not S9 activating enzymes were added. Five TNT metabolites gave statistically significant but small increases in mutation frequency over solvent controls: 4-amino-2,6 dinitrotoluene, 2,4',6,6'-tetranitro-2',4-azoxytoluene, 2,2',6,6'-tetranitro-4,4'-azoxytoluene, 2',4,6,6'-tetranitro-2,4'-azoxytoluene and triaminotoluene. Clear dose-response relationships could not be established for the mutagenic response of these compounds. They are considered as very weak mutagens in this mammalian test system. Five compounds did not produce statistically significant mutation frequencies at the levels tested: 2-amino-4,6-dinitrotoluene, 2,4-diamino-6-nitrotoluene, 1,3,5-trinitrobenzene, 2,6-diamino-4-nitrotoluene and 4,4',6,6'-tetranitro-2,2'-azoxytoluene. The results indicate that none of the TNT metabolites tested pose a significant mutational health risk, at least as judged by the CHO-hprt assay.

Animals↗

PubMedDate not supplied

Safety and optimum concentration of a manganese chloride-based oral MR contrast agent.

To determine the safety of a manganese chloride-based oral magnetic resonance (MR) contrast agent and the ideal concentration of the agent for marking in three different anatomic sites (stomach, middle of the small bowel, and ileocecal region), six healthy volunteers were evaluated before and after administration of 900 mL of three different concentrations of the contrast agent. Images were evaluated subjectively and objectively. No adverse events were noted. There was a minimal rise in manganese blood levels at 6 hours after administration, with a return to baseline at 24 hours. The imaging data demonstrated good-to-excellent bowel marking on T1-weighted images at all three concentrations. However, on T2-weighted images, the 40 mg Mn+2/L concentration provided improved hypointense bowel marking relative to the 20 mg/L concentration. Little difference was seen between the 40 and 60 mg/L concentrations. Fast T1- and T2-weighted sequences provided superior image quality to that of conventional spin-echo sequences.

Administration, Oral↗

PubMedDate not supplied

Catecholamine biosynthesis and vasopressin and oxytocin secretion in the spontaneously hypertensive rat: an in vitro study of localized brain regions.

The in vitro synthesis of catecholamines and the secretion of vasopressin (AVP) and oxytocin (OT) was measured in localized regions of the hypothalamo-neurohypophyseal system in the spontaneously hypertensive rat (SHR). The posterior pituitary (PP), median eminence (ME) and supraoptic (SON) and paraventricular (PVN) nuclear regions were incubated in vitro in media containing 3H-tyrosine. Media and tissue levels of AVP and OT were measured as well as norepinephrine and dopamine content and biosynthesis. There were no differences in peptide release in either the PP, ME or SON. However, there was a marked increase in peptide release from the PVN of the SHR. Media AVP levels were 0.3 pg/ml/micrograms protein in the WKY as compared to 2.1 pg/ml/micrograms protein in the SHR. OT release was increased 2 fold, from 0.85 to 1.7 pg/ml/micrograms protein. PVN content of both AVP and OT was significantly lower in the SHR. ME and SON peptide levels were not changed, while neurohypophyseal AVP levels were increased in the SHR. With regard to the catecholamines appreciable norepinephrine synthesis was measured in the PVN and SON while there was little 3H-norepinephrine in the ME or PP. In the hypertensive rat, there was an increase in norepinephrine synthesis in the PVN with no change in the SON. These results provide further support for fundamental changes in the catecholaminergic and peptidergic systems of the hypothalamo-neurohypophyseal axis of the SHR.

Animals↗

PubMedDate not supplied

Circadian rhythms of activity and drinking in mice lacking angiotensin II 1A receptors.

Angiotensin II (ANG II) type 1 receptors are found in the mouse suprachiasmatic nucleus (SCN), the site of the circadian pacemaker, but their significance for circadian timekeeping is unknown. We examined circadian rhythms of wheel running and drinking in angiotensin AT(1a) receptor knockout (KO) mice. Mean daily running and drinking activity were elevated in KO mice under a light-dark (LD) cycle and in constant dark (DD). These increases were confined to the usual active (dark) period, thus, the 'amplitude' of running and drinking rhythms was higher in KO mice. The phase of entrainment to LD (measured by the onset of the daily active period) did not differ between groups, either in LD or on the first day of DD ('unmasked' phase). KO mice showed a modestly shorter free-running period (tau) in DD. The direction and magnitude of phase shifts to light pulses at two circadian times (CTs) in DD did not differ between groups. Core functions of the circadian system appear intact following AT(1a) receptor KO. The modestly shorter tau and increased rhythm amplitude in KO mice may be secondary to an effect of the mutation on the level of running and drinking activity.

Animals↗

PubMedDate not supplied

Termination of resuscitation for traumatic cardiac arrest.

Explore the source record for details and available documents.

Age Factors↗

PubMedDate not supplied

Continuous transdermal dopaminergic stimulation in advanced Parkinson's disease.

The objective of the study was to determine the safety and efficacy of increasing doses of Rotigotine CDS in patients with advanced Parkinson's disease. The development of motor complications in Parkinson's disease has been linked to intermittent stimulation of dopamine receptors. Continuous, noninvasive, dopaminergic stimulation has not been available to date. Rotigotine CDS is a lipid-soluble D2 dopamine agonist in a transdermal delivery system that could fill this void. This inpatient study consisted of a 2-week dose escalation phase followed by a 2-week dose maintenance phase at the highest dose (80 cm2). Each individual's L-Dopa dose was back-titrated as feasible. The primary outcome measure was L-Dopa dose, and secondary outcome measures included early morning "off"-L-Dopa Unified Parkinson's Disease Rating Scale motor scores by a blinded evaluator and motor fluctuation data obtained from patient diaries ("on" without dyskinesia, "on" with dyskinesia, and "off"). Seven of 10 subjects provided data that could be evaluated. There were two administrative dropouts, and one individual was eliminated from the study because of recrudescence of hallucinations. The median daily L-Dopa dose decreased from 1,400 to 400 mg (p = 0.018, Wilcoxon test). Unified Parkinson's Disease Rating Scale motor scores were unchanged. Although diary variables improved in most individuals, only the reduction in "off" time attained statistical significance. Adverse effects were mild and consisted mainly of dopaminergic side effects and local skin reactions. The data suggest that Rotigotine CDS is an effective treatment for advanced Parkinson's disease and permits patients to substantially lower L-Dopa doses without loss of antiparkinsonian efficacy. Full-scale controlled clinical trials are warranted. In addition to potential therapeutic benefits, this drug can be used to test the hypothesis that continuous dopaminergic stimulation from the initiation of Parkinson's disease therapy will limit the development of motor complications.

Administration, Cutaneous↗

PubMedDate not supplied

Splenic imaging with ultrasmall superparamagnetic iron oxide ferumoxtran-10 (AMI-7227): preliminary observations.

PURPOSE: Ferumoxtran-10 (ultrasmall superparamagnetic iron oxide; Combidex, AMI-7227) is a long-circulating MR contrast agent with reticuloendothelial uptake known to enhance tissue T1 and T2 relaxation rates. The purpose of this study was to assess the effect of ferumoxtran-10-enhanced MRI in evaluating focal splenic lesions. METHOD: Eighteen patients underwent MR evaluation of the spleen. Two of these patients with exophytic normal splenic tissue (splenules) and 13 of these patients with 24 focal splenic lesions (7 cysts, 2 hemangiomas, 7 metastases, 1 infarct, 7 lymphoma) were assessed by T1-weighted gradient echo and T2-weighted fast SE MRI following intravenous administration of ferumoxtran-10 (1.1 mg of Fe/kg). Qualitative analysis involving improved lesion detection and/or characterization, additional information from postcontrast images affecting staging, and patient management was performed. Quantitative measurements of lesion-to-spleen contrast-to-noise ratio were also performed. RESULTS: Additional information was provided by ferumoxtran-10-enhanced images in 15 of 18 patients. In 8 of 15 (53%) patients, improved lesion detection (i.e., number of lesions) was obtained on contrast-enhanced images. Improved lesion visualization (i.e., conspicuity) was noted in 11 of 15 (73%) of patients. In 10 of 15 (67%) patients, postcontrast imaging provided additional information leading to lesion characterization. Staging of disease and patient management were affected in 5 of 15 (33%) and 6 of 15 (40%) patients, respectively. CONCLUSION: Ferumoxtran-10 is a promising contrast agent for the evaluation of focal splenic lesions.

Adult↗

PubMedDate not supplied

Melatonin receptors and signal transduction mechanisms.

The ovine pars tuberalis (PT) still offers the best model for the study of signal transduction pathways regulated by the melatonin receptor. From the evidence accumulated so far, it seems likely that the cAMP signal transduction pathway will be a major effector of a stimulatory signal to the PT which can be regulated by melatonin. Thus a principal action of melatonin in the PT may be the repression of biochemical processes driven by cAMP. However, through the phenomenon of sensitization, melatonin may also act to amplify a stimulatory input to the cAMP signal transduction pathway in the PT. These events are mediated via the melatonin receptor, which is itself a target for regulation by the melatonin signal. Studies using the PT have identified several signalling pathways that may serve to positively or negatively regulate the expression of the melatonin receptor. These and other studies in the PT have alluded to cAMP-independent pathways regulated by the melatonin receptor.

Animals↗

PubMedDate not supplied

Neurohypophyseal response to dehydration in the spontaneously hypertensive rat.

Experiments were performed to evaluate the effect of dehydration on neurohypophyseal hormone secretion, both vasopressin and oxytocin, fluid balance, and blood pressure in male spontaneously hypertensive rats (SHR) and their normotensive controls, Wistar Kyoto (WKY). Metabolic studies showed that the antidiuretic response to dehydration (24 and 48 hours of water deprivation) was significantly depressed (p less than 0.01) in the hypertensive animals. They responded inappropriately to dehydration with a greater loss of water and sodium and a larger increase in hematocrit. In contrast, the vasopressin response (both urinary excretion and plasma levels) was increased. The peak plasma levels were 25.3 pg/ml (SHR) compared to 16.6 pg/ml (WKY), while the urinary excretion was 22.5 ng/24 hrs (SHR) vs 9.0 ng/24 hrs (WKY). Dehydration also elicited a stimulation of oxytocin secretion, with no differences observed in the responses of the groups. Blood pressure was significantly greater in the SHR and it did not change during dehydration. These results provide further support for the idea that hypertension is associated with abnormalities in the control of fluid/electrolyte balance.

Animals↗