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Biomedical subjects

D M Wright

Publications and source records attributed to D M Wright.

At least 19 recordsLinked to original sources
PubMed1992

Reproductive and developmental toxicity of N,N-diethyl-m-toluamide in rats.

N,N-Diethyl-m-toluamide (mDET, DEET) is widely used as a topical insect repellent. It is the active ingredient in many consumer formulations, which usually contain 10-25% mDET in an alcohol base. More concentrated consumer products are also available, including some that are pure technical grade mDET. Persons living or employed in mosquito-infested areas may have very high seasonal exposures to mDET. Because contradictory reports had been published on the reproductive and developmental toxicity of mDET, a series of studies was conducted in male and female Sprague-Dawley rats. All treatments were administered by daily subcutaneous injections of undiluted mDET. A dose finding study was done using 12 time-mated females per group treated on Gestational Days (GD) 6-15 with 0.50, 0.62, 0.78, 0.92, or 1.2 ml mDET/kg/day. No females survived 10 days of mDET dosing with 1.2 ml/kg/day. Deaths occurred in all other groups except the low dose (0.50 ml/kg/day). Pregnant females treated on GD 6-15 with 0 or 0.30 ml/kg/day were used for the teratology study. Half of each group was euthanized on GD 20: the second half was singly housed in nesting boxes and allowed to deliver litters. Live pups were counted and weighed soon after birth on Postnatal Day (PD) 0 and again on PD 3, 9, and 14. Proven fertile males were treated 5 days/week for 9 weeks with 0, 0.30, 0.73, 1.15, or 1.80 ml mDET/kg/day for a male dose-finding study. Each group consisted of 20 males. No males survived the 1.80 ml/kg/day. Deaths occurred in all remaining dose groups except the 0.30 ml/kg/day and control group. Immediately following the final treatment of the male dose study, 11 males were randomly selected from the 0.30 and 0.73 ml/kg/day groups. They were cohabited for 7 days with 4 females per male during post-treatment Weeks 1 and 2. Half of the females were euthanized 12-14 days after the last day of cohabitation for a dominant lethal study; the remaining females were singly housed in nesting boxes and allowed to deliver litters. Live pups were counted and weighted on PD 0 and 3. There was no evidence of reproductive or developmental toxicity in any of these assays, but there were signs of neurotoxicity in treated adult male and female rats, which may relate to reports of neurotoxicity in humans heavily exposed to mDET-containing insect repellents.

Abnormalities, Drug-Induced↗
PubMed1992

Methods of monitoring menstrual function in field studies: efficacy of methods.

Efficacy of methods for monitoring female reproductive potential under field study conditions was evaluated. Women (n = 10) were recruited to participate for two menstrual cycles on the bases, in part, of not seeking fertility assistance, working full-time but not in the medical field, and having less than one year of college education. Luteinizing hormone (LH), estrone-3-glucuronide, and pregnanediol-3-glucuronide were measured in daily morning urine and normalized to creatinine concentrations. These urinary measures were parallel to serum LH, estradiol, and progesterone profiles. Based on these urinary measures, 6 of 19 cycles were judged to be atypical. Transvaginal ultrasonography provided insights into ovarian activity during the atypical cycles. Of 13 LH surges detected by radioimmunoassay, 7 were not detected by a semiquantitative dipstick (OvuSTICK), perhaps due to that method's sensitivity to loss of LH immunoactivity caused by sample freezing. While intervals from salivary and vaginal mucous electrical resistance signals to the LH surge during typical cycles were similar to those reported previously, they were not predictive of ovulatory status during atypical cycles. Fifty-three percent of the cycles were misclassified on the basis of the basal body temperature rise. Cervical mucous color, amount, and consistency were not predictive of ovulation under these study conditions. The results from these 19 menstrual cycles provide information about the efficacy of various methods for characterizing menstrual function under field study conditions. In this regard, urinary endocrine measures are the most informative or practical.

Adult↗
PubMed1992

Methods of monitoring menstrual function in field studies: attitudes of working women.

This study was designed to determine the attitudes and compliance of working women toward methods being evaluated for use in the assessment of the effects of toxicants on reproductive potential. Women such as the highly motivated fertility patients and nurses, who are typically familiar with the methods and procedures of fertility assessment and the value of medical research, have been used to validate such methods in a clinical setting. However, the attitudes of a general working female population toward these methods are unknown. Nine participants were selected on the bases, in part, of not seeking fertility assistance, working full-time but not in the medical field, and having less than one year of college education. Attitudes were also evaluated for 193 non-participating women to whom the procedures had been verbally described. Participants measured basal body temperature and salivary and vaginal mucous electrical resistance, evaluated cervical mucus manually (CME), and collected the first morning urine for two menstrual cycles. Blood, saliva, and transvaginal ultrasonograms (US) were obtained at a fertility clinic 6 to 9 days per cycle. Participants brought urine to the laboratory every 3 days. All participants performed all methods. Participants were paid $400; nonparticipants were not compensated. Only 3% of the respondents objected to the proposed methods: principally to CME, US, and giving blood samples. No respondent perceived the study as unimportant.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Management of theophylline overdose patients in the intensive care unit.

In a retrospective survey of all adults admitted to the Intensive Care Unit with acute theophylline poisoning over the last five years, we identified 38 patients (6.8% of all admissions for poisoning), two of whom died. Thirty-five (92%) had taken a sustained-release preparation. Eight patients had grand mal seizures and six developed arrhythmias (ventricular fibrillation, 3; atrial fibrillation, 2; supraventricular tachycardia, 1). Severe vomiting was present in 34 (89%) and proved to be a serious obstacle to the administration of enteral charcoal. The vomiting was controlled by intravenous metoclopramide in seventeen patients (50%), but the remaining seventeen required mechanical ventilation with sedation and muscle relaxation for the effective delivery of nasogastric charcoal. Importantly, in nine (24%), the serum theophylline concentration continued to rise despite enteral charcoal. Charcoal haemoperfusion was used in seven (18%). We present an algorithm for the management of severe, acute theophylline poisoning.

Absorption↗
PubMed1991

The prospero gene specifies cell fates in the Drosophila central nervous system.

The molecular mechanisms used to generate neuronal diversity are largely unknown. To identify genes controlling cell fate in the Drosophila central nervous system, we screened for mutations that alter expression of homeobox genes in the developing central nervous system (indicating changes in cell fates). We also screened "enhancer trap" lines to identify genes expressed in neuronal stem cells (neuroblasts). The prospero gene was discovered in both screens. prospero is expressed in a subset of neuroblasts, sensory neuron precursors, and identified glial precursors. It is not expressed in neurons. Neuroblasts lacking prospero function generate abnormal cell lineages, producing incorrectly specified progeny that differentiate into neurons showing axon pathfinding defects. prospero is therefore a novel type of gene expressed in neuroblasts and known to specify neuronal fate.

Animals↗
PubMed1991

Mechanism of diuretic action of spiradoline (U-62066E)--a kappa opioid receptor agonist in the human.

1. The mechanism of the diuretic effect of the kappa opioid receptor agonist spiradoline was investigated in 10 healthy male subjects in a placebo-controlled, double-blind cross-over study. 2. Urine volume and osmolality, plasma vasopressin and Doppler renal blood velocity indices were recorded for 1.25 h before and 6 h following injection. 3. Spiradoline caused a significant increase in urine output which was antagonized by high but not low dose naloxone. The urine increase was accompanied by a significant decrease in osmolality which was also antagonised by high but not low dose naloxone. 4. Spiradoline had no effect on plasma vasopressin concentration or on renal blood velocity indices. 5. We conclude that kappa agonists induce diuresis in humans by a mechanism not involving suppression of vasopressin or changes in renal blood velocity indices.

Adult↗
PubMed1991

The prospero gene encodes a divergent homeodomain protein that controls neuronal identity in Drosophila.

The Drosophila central nervous system (CNS) develops from a population of stem cells called neuroblasts; each neuroblast goes through an invariant cell lineage to produce a characteristic family of neurons or glia. We are interested in the molecular mechanisms controlling neuroblast cell lineage. Recently we identified the prospero (pros) gene, which is expressed in embryonic neuroblasts. Loss of pros function results in aberrant expression of the homeobox genes fushi tarazu, even-skipped and engrailed in a subset of neuroblast progeny, suggesting that pros plays an early and fundamental role in the specification of neuronal fate (Doe et al. 1991). Here we show that the pros gene encodes a highly divergent homeodomain. The homeodomain contains several of the most conserved amino acids characteristic of known homeodomains, yet it is considerably less basic than previously identified homeodomains. These data are consistent with a model in which pros controls neuroblast cell lineages by regulating gene expression.

Amino Acid Sequence↗
PubMed1987

Repeated hemoperfusion and continuous arteriovenous hemofiltration in a paraquat poisoned patient.

Prompt hemodialysis or hemoperfusion can be of value during the first 24 hours after paraquat ingestion particularly when the patient has developed acute renal failure. However, many cases of paraquat poisoning occur in areas where hemoperfusion facilities are unavailable. In contrast, continuous arteriovenous hemofiltration (CAVH) could be instituted easily. We have measured the removal of paraquat from the body by CAVH in a 46 year old male cane farmer who ingested 70 ml, 20% paraquat and died twelve days later from pulmonary fibrosis. Renal failure developed rapidly. Concentrations of paraquat were measured by an indirect competitive ELISA using a murine paraquat monoclonal IgG antibody. Hemoperfusion was performed daily for five days, beginning 78 hours post-ingestion. By 180 hours, when the patient was in respiratory failure, hemoperfusion was replaced with CAVH which was continued for 46 hours. During this time interval, 1.1 mg paraquat was recovered in the hemofiltrate and 1.56 mg paraquat in the urine. The extraction of paraquat by the hemofilter was close to 100%. The plasma clearance of paraquat across the hemofilter was 6.1 ml/min and the renal clearance was 8.2 ml/min. The mean hemoperfusion clearance of paraquat was 50 ml/min and the total amount of paraquat removed by the 34 hours of hemoperfusion was 9 mg. Because of the relative ease with which CAVH can be performed, its low cost, compared to that of hemoperfusion or hemodialysis, and the continuous nature of the procedure, CAVH may be worth considering in paraquat poisoning. It could be used particularly in those patients who have developed renal failure or while patients are being prepared for hemoperfusion.

Hemofiltration↗
PubMed1986

Zinc and paired-pulse potentiation in the hippocampus.

Zinc was added to the perfusate of rat hippocampal slices to determine the effect on the potentiation of evoked responses in subfield CA3 following paired-pulse stimulation of mossy fibres. Paired-pulse potentiation across a range of interpulse intervals and currents was significantly depressed by 50 and 500 microM zinc chloride. Additionally but only at the higher concentration, the amplitude of the first evoked potential was significantly increased. These results provide further evidence of a role for zinc in hippocampal neurotransmission.

Animals↗
PubMed1986

Effect of zinc on neuronal activity in the rat forebrain.

Zinc ions, which are unevenly distributed in the CNS and can be released from nerve terminals, have been implicated as causative agents in epileptogenesis. The present study has shown that intraventricular administration to anesthetized rats causes seizure activity of the ECOG and convulsions. Since the manner in which zinc influences neuronal activity and triggers convulsions is unclear, studies were also made of its effect on spontaneous and evoked activity in the rat forebrain. It was found that iontophoretic application of zinc to cortical neurons causes slow and often prolonged increases in firing rate, usually accompanied by bursts of high frequency discharge in just under half the studies. Another cation, barium, evoked excitatory responses of a similar type and a reduction in potassium permeability may underlie the effects of both cations. In contrast, calcium, magnesium, manganese and cerium caused short duration depressant effects. The depression induced by calcium, but not by the other cations, could be blocked by zinc. Similarly, in the hippocampus zinc depressed calcium-dependent potentiation in subfield CA3 evoked by paired-pulse stimulation of mossy fibers; excitatory effects (namely an increase in spike amplitude and appearance of multiple population spikes) were seen at higher zinc concentrations. The depressant effects of an enkephalin analog on cortical firing rate were also blocked by zinc, consistent with studies from another laboratory suggesting enkephalin/zinc interactions. In contrast, the depressant effect of GABA could not be blocked by zinc, although an antagonism has been reported in the lobster muscle. Firm conclusions regarding the mechanism(s) underlying the triggering of seizure activity by zinc cannot yet be drawn, but the results of these studies would be consistent with an interference with calcium and/or potassium ion activity rather than with GABA binding sites.

Action Potentials↗
PubMed1985

Stress-induced analgesia evoked by intraperitoneal injection of hypertonic saline: evidence for its occurrence in vasopressin deficient rats.

Experiments were carried out to investigate whether vasopressin is involved in stress-induced analgesia. Intraperitoneal injection of hypertonic saline caused a significant and dose-related increase in the latency to the tail-flick response of the rat to noxious heat and was used as a stimulus for stress-induced analgesia. Neither the pituitary nor opioid peptides appeared to be involved, since the response occurred in hypophysectomized rats and was not reduced by the opiate antagonist naloxone. Furthermore hypertonic-saline analgesia was clearly potentiated in hypophysectomized rats in comparison to sham-operated controls. Hypertonic-saline analgesia was also observed in vasopressin-deficient (homozygous Brattleboro) rats similar in both magnitude and duration to that in normal rats of the same strain (Long Evans). It was concluded that vasopressin was not involved in stress-induced analgesia evoked by hypertonic saline.

Animals↗
PubMed1985

Evidence for a spinal site at which opioids may act to inhibit the milk-ejection reflex.

Morphine was injected into the lumbar subarachnoid space of anaesthetized lactating rats (7-10 days post partum) to examine its effect on the milk-ejection reflex at a spinal level. Although the delay until the first milk-ejection response to the suckling of hungry pups was variable (3-60 min) the subsequent responses occurred at regular intervals of 7.5 +/- 0.4 min; milk-ejection responses were detected by measurement of intramammary pressure and by the characteristic behaviour of the pups. Injection of morphine (4-50 micrograms) via a cannula inserted into the spinal subarachnoid space inhibited reflex milk ejection in a dose-related manner without affecting the sensitivity of the mammary gland to exogenous oxytocin (1 mu., i.v.); injection extradurally was without effect. The opiate antagonist naloxone (10 micrograms), when injected intrathecally, did not significantly alter the pattern of reflex milk ejection or the amplitude of the intramammary pressure response, but prevented the inhibitory effect of morphine when administered with the opiate. Pethidine (250 and 400 micrograms) also inhibited the milk-ejection reflex. It is unlikely that the effect of spinal administration of morphine occurred as the result of the transportation to a supraspinal site since release of oxytocin evoked by intraventricular injection of hypertonic sodium chloride (3 mol/l) was blocked by intraventricular injection of morphine (4 micrograms) but not by a much larger dose (40 micrograms) injected intrathecally.

Animals↗
PubMed1984

Zinc: effect and interaction with other cations in the cortex of the rat.

Zinc and other cations were iontophoretically applied to neurones in the frontoparietal cortex of urethane-anaesthetised rats and their effect on the activity of these cells was examined. Slow and often prolonged increases in firing rate occurred in 45.2% of neurones after zinc application and 72.7% after barium. Calcium caused short duration decreases in firing rate in 89.3% of neurones as did manganese (78.6%) cerium (21.9%) and magnesium (33.3%). When applied simultaneously zinc blocked the depressant effect of calcium (in 79.3% of neurones) but not that of manganese or GABA; other ions were ineffective. These results suggest that zinc, which is known to be present in nerve terminals, may modulate neuronal activity.

Animals↗
PubMed1984

Inhibition of oxytocin secretion by mu and delta receptor selective enkephalin analogues.

The effects on oxytocin release of enkephalin analogues, thought to be highly selective agonists of the mu or delta opioid receptor, were compared. Oxytocin release was evoked in urethane-anaesthetised rats (7-10 days post partum) by intracerebroventricular injection of NaCl (3M) at 15-20 min. intervals and detected by the resultant increase in intramammary pressure. Enkephalin analogues (the mu receptor agonist Tyr-D-Ala-Gly-MePhe-NH (CH2)2OH (DAGO), the delta receptor agonist (D-Ala2-D-Leu5) - enkephalin (DADLE) and metkephamid, which has been reported to be particularly efficacious at the delta receptor) were administered intracerebroventricularly 3-5 min. prior to hypertonic saline. Oxytocin release was inhibited in a dose-dependent, naloxone-reversable manner by DAGO (ED50 : 40ng), DADLE (ED50 : 156ng) and metkephamid (ED50 : 42ng); the mammary gland sensitivity to oxytocin was unaffected. These results suggest that the inhibitory action may be mediated through both mu and delta receptors and provide further evidence in support of a role of enkephalins in the control of oxytocin secretion.

Animals↗
PubMed1984

A comparison of analgesia and suppression of oxytocin release by opiates.

The potency of opiates for suppressing oxytocin release relative to their potency as analgesics was tested in lactating rats. Oxytocin release was evoked by the sucking of the young in urethane-anaesthetized and unanaesthetized rats, and was detected by the characteristic behaviour of the young and milk yield respectively. The tail-flick test, using noxious radiant heat, was used to assess analgesia. Intraperitoneal injection of morphine (1 mg kg-1 and 5 mg kg-1) significantly reduced milk yield in unanaesthetized rats. Urethane-anaesthetized rats displayed a pattern of reflex milk-ejection responses similar to that found in conscious rats. This reflex was significantly inhibited in a dose-related, naloxone-reversible manner by buprenorphine (ED50 0.18 mg kg-1), meptazinol (ED50: 14.0 mg kg-1), morphine (ED50: 0.67 mg kg-1), pentazocine (ED50: 15.0 mg kg-1) and pethidine (ED50: 7.9 mg kg-1). Although intraperitoneal injection of morphine (5 mg kg-1) abolished the increase in intramammary pressure occurring at reflex milk-ejection, that evoked by intravenous oxytocin (0.5-1 mu) was unaffected. Each opiate also caused significant, dose-related, naloxone-reversible increases in tail-flick latency. The ED50 doses were buprenorphine (ED50: 0.14 mg kg-1), meptazinol (ED50: 12.5 mg kg-1), morphine (ED50: 5.0 mg kg-1), pentazocine (ED50: 12.5 mg kg-1) and pethidine (ED50: 6.1 mg kg-1). The order of potency for analgesia and for suppression of oxytocin release were identical, namely: buprenorphine greater than morphine greater than pethidine greater than meptazinol greater than pentazocine. The results obtained with lactating rats suggest that secretion of the hormone oxytocin is substantially reduced during opiate-induced analgesia.

Analgesia↗
PubMed1983

Effect of ACTH on opiate inhibition of oxytocin release.

beta-Endorphin (200ng), dynorphin1-17 (2 micrograms) and morphine (4 micrograms) suppressed the osmotically-evoked release of oxytocin in anaesthetized lactating rats. ACTH1-24 (0.2-3 micrograms) administered intraventricularly 3 min before beta-endorphin or morphine attenuated their inhibitory action, but when applied afterwards was never seen to reverse their effects although this was achieved with naloxone (lmg X kg-1, i.v.). ACTH however, was ineffective against dynorphin. At higher doses an opiate-like action of ACTH was observed. Thus ACTH may act as a partial antagonist and at higher doses as a partial agonist of the opiate receptor for which it is known to have an affinity. It is suggested that suppression of oxytocin release by endogenous beta-endorphin could be modified by ACTH with which it may be co-released.

Adrenocorticotropic Hormone↗