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Identification of specific cell types is fundamental to interpreting single cell recording studies. The hypothalamic supraoptic nucleus (SON) contains phasic (putative vasopressin) cells and a mixed population of continuously firing vasopressin and oxytocin cells. We injected cholecystokinin (CCK-8; i.v.), which is known to release oxytocin but not vasopressin, to see if such injections might differentiate oxytocin from vasopressin cells. Recordings made, using the ventral surgical approach to the SON in female rats under urethane anaesthesia (1.3 g/kg) from 49 non-phasic cells showed that CCK-8 (20 micrograms/kg) excited 41. Twenty of these 41 cells were tested for their response to i.v. injections of phenylephrine (10 micrograms), which interrupts the firing of putative vasopressin cells, and none were inhibited. Only one out of 8 cells recorded from suckled, lactating rats which showed a burst of spikes just before reflex milk-ejection was inhibited by phenylephrine. Injections of CCK-8 also excited 4 out of four such 'milk ejection' cells. Cells activated by CCK, cells unaffected by phenylephrine, cells activated just before reflex milk-ejection and cells which fire continuously appear to be a single population, thus continuous firing gives a good indication that an SON cell secretes oxytocin.
Pethidine (also known as meperidine and as Demerol) injected subcutaneously at 10 mg/kg into parturient rats on the birth of the second pup resulted in a marked slowing of the progress of parturition, associated with reduced plasma oxytocin concentrations. Injection of the opiate antagonist naloxone counteracted the inhibition of oxytocin secretion and largely prevented the slowing of parturition. In vitro, pethidine inhibited spontaneous, oxytocin-induced and acetylcholine-induced contractions of uteri from rats immediately post partum, and these effects were not reversed by naloxone. In anesthetized lactating rats, pethidine inhibited the suckling-induced milk-ejection reflex and attenuated oxytocin-induced contractions of mammary myoepithelium. Finally, pethidine depressed plasma oxytocin concentrations in rats given 2% saline to drink for 24 h to stimulate oxytocin secretion. Thus pethidine inhibits oxytocin secretion in all three conditions; this inhibition is probably mediated by central opioid receptors. In addition, however, pethidine depresses the oxytocin responsiveness both of mammary myoepithelium and of myometrium. The latter effect at least is not opioid mediated.
Urethane anaesthetized male rats were given an i.p. injection of hypertonic saline to increase plasma osmotic pressure. This injection resulted in significantly elevated plasma oxytocin levels and increased discharge activity of putative oxytocin cells in the supraoptic nucleus. Subsequent injection of naloxone (1 mg/kg) i.v. resulted in a similarly large increase in plasma oxytocin, but did not affect the discharge activity of putative oxytocin neurones. The results suggest that, following an i.p. injection of hypertonic saline, endogenous opioids act at the neurosecretory terminals to partially inhibit oxytocin release.
The influence of a number of clinical characteristics on the population pharmacokinetics of gentamicin were examined using routine drug-monitoring data from a group of 113 neonates. The data were analyzed using the programme NONMEM. Clearance was 0.053 litres.h-1.kg-1 and was reduced in neonates with postconceptional age less than or equal to 34 weeks (X 0.83) and 5-min Apgar score less than 7 (X 0.82). Volume of distribution was 0.47 litres.kg-1. These population mean parameter estimates were used to generate dosage regimens to achieve concentrations within the therapeutic range.
The number of Na+-independent, Cl--dependent glutamate binding sites in rat hippocampal membranes is increased two- to fourfold after pre-exposing isolated membranes or hippocampal slices to high concentrations (0.1-10 mM) of L-glutamate or of glutamate analogs with high affinity for this binding site, such as quisqualate, homocysteate, or aminoadipate. N-Methylaspartate and kainate are ineffective. A similar binding increase is induced by transient exposure to the dipeptide tyrosylglutamate. The newly induced binding sites appear to be identical with pre-existing Cl--dependent binding sites by several criteria: They have a similar pharmacological profile, they are sensitive to low concentrations of Na+, and the number of sites can be further increased by transient exposure to micromolar calcium concentrations. Moreover, binding of [3H]APB, a ligand selective for the Cl--dependent glutamate binding sites, is also increased after glutamate preincubation. The induction of binding sites by high glutamate concentrations, described herein, is calcium-independent, not inhibited by leupeptin and, therefore, different from the previously described activation of binding sites by a calcium-sensitive protease. The high concentration of ligand needed to induce increased binding suggests the presence in hippocampal membranes of a binding site with low, millimolar affinity that is functionally related to the known high-affinity binding sites. Several interpretations of the observed effects and their implications for the possible relationship between the binding site and the synaptic receptor are discussed.
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The results of treating 59 patients with advanced carcinoma of the cervix with Adriamycin and methotrexate are given. Five combinations of the two cytotoxic drugs have been evaluated, differing only with regard to the methotrexate. One particular regimen has been shown to be effective with a relatively high remission rate coupled with a low rate of side effects.
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In six women who had had a hysterectomy and three or more vaginal smears positive for malignant cells but no symptoms, a course of immunotherapy, based on delayed hypersensitivity reaction to dinitrochlorobenzene, was tried. Repeat smears done every three months have all been normal, and the patients were well when last seen 2-35 months after treatment.
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