Phase III safety study of intravenous NEPA: a novel fixed antiemetic combination of fosnetupitant and palonosetron in patients receiving highly emetogenic chemotherapy.

Background: NEPA, an oral fixed combination of the NK1RA netupitant (300 mg) and clinically/pharmacologically distinct 5-HT3RA palonosetron (PALO, 0.50 mg), is the first fixed antiemetic combination to have been approved. A single oral NEPA capsule plus dexamethasone (DEX) given before anthracycline-cyclophosphamide (AC) and non-AC highly emetogenic chemotherapy (HEC) showed superior prevention of chemotherapy-induced nausea and vomiting (CINV) over PALO plus DEX for 5 days postchemotherapy. The safety of NEPA was well-established in the phase II/III clinical program in 1169 NEPA-treated patients. An intravenous (i.v.) formulation of the NEPA combination (fosnetupitant 235 mg plus PALO 0.25 mg) has been developed. Patients and methods: This randomized, multinational, double-blind, stratified (by sex and country) phase III study (NCT02517021) in chemotherapy-naïve patients with solid tumors assessed the safety of a single dose of i.v. NEPA infused over 30 min before initial and repeated cycles of HEC. Patients received either i.v. NEPA or oral NEPA, both with oral DEX on days 1-4. Safety was assessed primarily by treatment-emergent adverse events (AEs) and electrocardiograms. Results: A total of 404 patients completed 1312 cycles. The incidence and type of treatment-emergent AEs were similar for both treatment groups with the majority of AEs as mild/moderate in intensity. There was no increased incidence of AEs in subsequent cycles in either group. The incidence of treatment-related AEs was similar and relatively low in both groups (12.8% i.v. NEPA and 11.4% oral NEPA during the entire study), with constipation being the most common (6.4% i.v. NEPA, 6.0% oral NEPA). No serious treatment-related AEs occurred in either group. No infusion site or anaphylactic reactions related to i.v. NEPA occurred. No clinically relevant changes in QTc and no cardiac safety concerns were observed. Conclusions: Intravenous NEPA was well-tolerated with a similar safety profile to oral NEPA in patients with various solid tumors receiving HEC.

Dynamic social support networks of younger black men who have sex with men with new HIV infection.

Rising rates of HIV infection among younger black men who have sex with men (YBMSM) in the USA have generated a public health emergency. Living with HIV requires deep and persistent social support often available only from close confidants. Enlisting endogenous support network members into the care of HIV-infected YBMSM may help shape sustainable supportive environments, leading to long-term improvements in mental and HIV-specific health outcomes. The present study examined trends in support network change over time after new HIV diagnoses among 14 YBMSM. Participants completed a social network survey that utilized sociograms to record support confidants (SCs) preceding HIV diagnosis and at one and nine months postdiagnosis. Reported SCs included family of origin, friends, sex partners, and other associates. Analysis revealed three distinct patterns of change: high gain, high turnover, and stable networks. These patterns offer valuable insights into the social support of YBMSM during the period following diagnosis. This research underscores a growing movement to embrace key support figures in the lives of YBMSM, who may be critical to promoting overall health and adherence to HIV-care.

Coincident detection of CSF Na+ and osmotic pressure in osmoregulatory neurons of the supraoptic nucleus.

Behavioral and neuroendocrine responses underlying systemic osmoregulation are under the concerted control of centrally located osmoreceptors and cerebrospinal fluid (CSF) Na+ concentration ([Na+]) detectors. Although the process underlying osmoreception is understood, the mechanism by which [Na+] is detected and integrated with cellular information derived from osmoreceptors is unknown. Here, we show that shifts in extracellular [Na+] ([Na+]0) cause proportional changes in the relative Na+ permeability of mechanosensitive cation channels responsible for signal transduction in the osmosensory neurons of the supraoptic nucleus. This effect causes the generation of Na+ specific receptor potentials under isotonic conditions and modulates osmoreceptor potentials and electrical responsiveness during osmotic perturbation. These results provide a cellular basis for Na+-sensing and for the coordinated detection of CSF [Na+] and osmolality in central osmoregulatory neurons.

A role for wind-up in trigeminal sensory processing: intensity coding of nociceptive stimuli in the rat.

Wind-up is a progressive, frequency-dependent increase in the excitability of trigeminal and spinal dorsal horn wide dynamic range (WDR) nociceptive neurons evoked by repetitive stimulation of primary afferent nociceptive C-fibres. The correlate of wind-up in humans is temporal summation, which is an increase in pain perception to repetitive constant nociceptive stimulation. Although wind-up is widely used as a tool for studying the processing of nociceptive information, including central sensitization, its actual role is still unknown. Here, we recorded from trigeminal WDR neurons using in vivo electrophysiological techniques in rats and assessed the wind-up phenomenon in response to stimuli of different intensities and frequencies. First, we found that the amplitude of C-evoked responses of WDR neurons to repetitive stimulation increased progressively to reach a peak, then consistently showed a stable or slightly decreasing plateau phase. Only the first phase of this time course fitted in with the wind-up description. Therefore, to assess wind-up, we measured a limited number of initial responses. Second, we showed that wind-up, i.e. the slope of the frequency-dependent increase in the response to C-fibre stimulation, was linearly correlated to the stimulus intensity. Intensities of brief C-fibre inputs were thus coded into frequencies of action potentials by second-order neurons through frequency-dependent potentiation of the evoked responses. Third, wind-up also occurred at stimulation intensities below the threshold for C-evoked responses in WDR neurons, suggesting that wind-up can amplify subthreshold C-fibre inputs to WDR neurons. This might account for the observation that sparse, subliminal, neuronal activity in nociceptors can become painful via central integration of neural responses. Altogether, the present results show that wind-up can provide trigeminal WDR neurons with the capability to encode the intensity of short-duration orofacial nociceptive stimuli and to detect subthreshold nociceptive input. Thus, not only may wind-up play a physiological role in trigeminal sensory processing, but its enhancement may also underlie the pathophysiology of chronic orofacial pain conditions.

Profile of monoamine and excitatory amino acid release in rat supraoptic nucleus over parturition.

The magnocellular oxytocin neurons of the hypothalamic supraoptic (SON) and paraventricular nuclei play an important role in the initiation and maintenance of parturition in the rat. As little is known about the neural inputs responsible for activating oxytocin neuron activity at this time, we used the technique of microdialysis to examine the profile of monoamine and excitatory amino acid neurotransmitter release within the SON before and during parturition. Microdialysis probes were implanted into the SON of anesthetized pregnant rats (n = 8) on the morning of the day preceding parturition (day 20), and 15-min dialysate samples were collected from freely moving animals over the following 2 days until 3 h after birth of the last pup. On the day of parturition (day 21), dialysate concentrations of norepinephrine were significantly increased (P < 0.05) in the hour leading up to the expulsion of the first pup and, compared with those on the previous day, remained at significantly (P < 0.05) elevated levels throughout the course of parturition. A significant (P < 0.01) increase in glutamate concentrations was also detected, although in this case, it was only elevated transiently in the 15-min period immediately before the onset of pup expulsion. Mean levels of dopamine were not different between days 20 and 21, but a significant increase in dopamine release was detected specifically during the second half of parturition. No significant changes in serotonin and aspartate concentrations were observed on days 20 and 21 or in relation to parturition. This study provides an analysis of neurotransmitter release in the SON over parturition and indicates that norepinephrine concentrations are elevated well in advance of the onset of pup expulsion, whereas a burst of glutamate release occurs immediately before the birth of the first pup. Such changes are likely to reflect activity in afferent inputs to the SON and may represent neurochemical events involved in the initiation and maintenance of parturition.

Sustained L-type calcium currents in dissociated deep dorsal horn neurons of the rat: characteristics and modulation.

Deep dorsal horn neurons present plateau properties involved in non-linear integration of nociceptive inputs, in the windup of the discharge, and in the expression of long-lasting afterdischarges. In vitro experiments using intracellular recordings in a slice preparation of the rat spinal cord have established that they are supported in part by voltage-dependent calcium currents, and positively modulated by metabotropic glutamate receptor activation. In the present study, whole-cell patch-clamp recordings in acutely isolated soma of dorsal horn neurons (n=48) were used to analyse the voltage-dependent calcium currents involved.Deep dorsal horn neurons expressed both inactivating and non-inactivating calcium currents with Ca(2+) or Ba(2+) used as a charge carrier. The non-inactivating component activated at intermediate threshold (-55mV), and was blocked mostly by nifedipine (61+/-6%). Although voltage-dependent facilitation of whole-cell calcium currents could be obtained by prepulses to +100mV, repetitive depolarization at potentials compatible with the plateau (-45mV and -10mV) failed to induce facilitation of calcium currents. No direct modulation of somatic calcium currents by application of (S)-3,5-dihydroxyphenylglycine, a selective group I metabotropic glutamate receptor agonist and 1S,3R-1-amino-1,3-cyclopentanedicarboxylic acid, a group I and II metabotropic glutamate receptor agonist, was found, while application of the metabotropic GABA(B) receptor agonist baclofen induced a significant decrease in calcium currents.Thus, the present voltage-clamp study shows that rat deep dorsal horn neurons express a non-inactivating, nifedipine sensitive, intermediate threshold (-55mV) calcium current which could provide the depolarizing drive to generate plateau potentials near threshold. Our results also indicate that calcium currents are not sensitized following repetitive stimulation, and not modulated by metabotropic glutamate receptor activation. They provide, however, the first evidence for a direct modulation of voltage-gated calcium channels in dorsal horn neurons by GABA(B) receptor activation, which may contribute to the mechanism of baclofen's antinociceptive activity.

Extracellular GABA concentrations in rat supraoptic nucleus during lactation and following haemodynamic changes: an in vivo microdialysis study.

Morphological and pharmacological evidence suggest that the dense GABAergic innervation of the supraoptic nucleus is important for regulating the electrical activity of vasopressin and oxytocin neurons. We have employed the technique of intracranial microdialysis to examine extracellular GABA concentrations in the supraoptic nucleus of the anaesthetized rat and questioned whether differences exist in the dynamics of GABA release between virgin and lactating rats, and if events during lactation or following blood pressure manipulation alter endogenous GABA levels in this nucleus. No significant differences were detected between virgin and lactating animals in either basal or 100 mM potassium ion-evoked GABA release. The inclusion of the GABA uptake blocker nipecotic acid (0.5 mM) into the dialysate resulted in a six- to eight-fold increase (P < 0.01) in GABA outflow in both groups of animals. In lactating rats, GABA outflow measured at 4 min intervals was not altered during a 60 min period of suckling by a full litter of pups and no significant change in GABA outflow was detected in relation to individual milk ejections. In virgin rats, removal of 1.5-2 ml of blood resulted in a 30-60 mmHg fall in blood pressure and a non-significant decline in GABA outflow. Replacement of blood resulted in an abrupt 50 mmHg increase in blood pressure and a significant 22% increase in GABA outflow (P < 0.01), but no change in aspartate or methionine concentrations. Repeated intravenous injections of the alpha-adrenoceptor agonist, metaraminol, similarly evoked approximately 50 mmHg increments in blood pressure and a 26% increase in GABA outflow (P < 0.05). Electrical stimulation of the diagonal band of Broca for 10 min produced a two-fold increase in GABA outflow from the supraoptic nucleus (P < 0.05). These results show that the overall profile of basal and potassium-stimulated GABA concentrations in the supraoptic nucleus is not substantially different between lactating and virgin rats. In lactating animals we have found that GABA levels are not altered in response to suckling or at the time of high-frequency firing by oxytocin neurons to induce milk ejection. In contrast, our data further support the hypothesis that GABA inputs to supraoptic neurons are part of a baroreceptor reflex, relaying through the diagonal band of Broca, to signal periods of acute hypertension and inhibit the firing of vasopressin neurons. Such observations suggest the physiological importance of GABA inputs to the supraoptic nuclei and indicate that GABA may be used in a stimulus-specific manner to influence the activity of magnocellular neurons.

Identification of estrogen receptor-containing neurons projecting to the rat supraoptic nucleus.

Circulating estrogens influence the electrical and biosynthetic activity of the hypothalamic magnocellular neurons which synthesize vasopressin or oxytocin and regulate body fluid homeostasis and reproduction. As none of these magnocellular neurons express nuclear estrogen receptor in the rat, the present study has combined estrogen receptor immunocytochemistry with retrograde tracing techniques to examine whether the first-order neurons projecting to magnocellular neurons in the supraoptic nucleus may be receptive to estrogen. Green fluorescent latex microspheres (50 nl) were injected into the supraoptic nucleus of five ovariectomized rats. The largest numbers of retrogradely-labelled cells expressing estrogen receptor immunoreactivity were detected in the organum vasculosum of the lamina terminalis, anteroventral periventricular nucleus and medial preoptic nucleus where approximately 15% of all retrogradely-labelled cells were estrogen receptor-immunoreactive. Other prominent sites where double-labelled cells were detected were the median preoptic nucleus, subfornical organ, ventrolateral division of the hypothalamic ventromedial nucleus and the brainstem nucleus tractus solitarii. Triple labelling experiments in the caudal medulla revealed that the estrogen-receptive neurons of the nucleus tractus solitarii and ventrolateral medulla projecting to the supraoptic nucleus were not noradrenergic. These findings show that sub-populations of neurons projecting to the supraoptic nucleus express estrogen receptors. This provides immunocytochemical evidence that estrogen may regulate the activity of magnocellular oxytocin and vasopressin neurons in an indirect, trans-synaptic manner by influencing the activity of first-order neurons projecting to the supraoptic nucleus. The predominance of estrogen-receptive lamina terminalis and preoptic area inputs to the supraoptic nucleus suggests respective sites of estrogen action on magnocellular neurons in modulating fluid balance and reproductive function.

Up-regulation of nitric oxide synthase messenger RNA in an integrated forebrain circuit involved in oxytocin secretion.

The hypothalamo-neurohypophysial system contains high levels of neuronal nitric oxide synthase and this increases further during times of neurohormone demand, such as that following osmotic stimulation. Using double in situ hybridization, we demonstrate here an increase in the expression of nitric oxide synthase messenger RNA by oxytocin neurons, but not vasopressin neurons, of the supraoptic nucleus at the time of lactation, when oxytocin is in demand due to another neuroendocrine stimulus, the milk-ejection reflex. In addition, using immunocytochemical retrograde tracing, we show that neurons of the subfornical organ, median preoptic nucleus and organum vasculosum of the lamina terminalis, which project to the supraoptic nucleus, contain nitric oxide synthase. These three structures of the lamina terminalis, together with the hypothalamo-neurohypophysial system, make up the forebrain osmoresponsive circuit that controls osmotically-stimulated release of oxytocin in the rat. The expression of nitric oxide synthase messenger RNA in the lamina terminalis was also shown to increase during lactation. The increases in nitric oxide synthase messenger RNA were not apparent during pregnancy. These results provide evidence for an integrated nitric oxide synthase-containing neural network involved in the regulation of the hypothalamo-neurohypophysial axis. The expression of nitric oxide synthase messenger RNA increases in this circuit during lactation and correlates with a reduction in the sensitivity of the circuit to osmotic stimuli also present in lactation but not pregnancy. As nitric oxide is believed to attenuate neurohormone release, it seems that the increased nitric oxide synthase messenger RNA expression detected here during lactation at a time of high oxytocin demand may be involved in reducing the sensitivity of the whole forebrain circuit to osmotic stimuli.

Ascending connections from the caudal part to the oral part of the spinal trigeminal nucleus in the rat.

The brainstem trigeminal somatosensory complex, while sharing many common aspects with the spinal somatosensory system, displays features specific to orofacial information processing. One of those is the redundant representation of peripheral structures within the various subnuclei of the complex. A functional redundancy also exists since a single sensory modality, e.g. nociception, may be processed within different subnuclei. In the present study, we addressed the question whether anatomical connections from the caudal part to the oral part of the spinal trigeminal nucleus may support topographical and functional redundancy within the rat trigeminal somatosensory complex. The retrograde tracer tetramethylrhodamine-dextran was injected iontophoretically into the oral subnucleus of anaesthetised rats. Cell bodies labelled retrogradely from the oral subnucleus were observed in laminae III-IV and V of the ipsilateral caudal subnucleus consistently, and to a lesser degree in lamina I. Such a distribution of retrogradely labelled cells suggested that specific subsets of neurones may relay nociceptive information, and others non-nociceptive information. Furthermore, intratrigeminal connections conserved the somatotopic distribution of primary afferents in the two subnuclei. First, injections of tracer in the dorsomedial and ventrolateral parts of the oral subnucleus resulted in retrograde labelling of the dorsal and ventral parts of the caudal subnucleus respectively. Second, animals that received tracer into the ventrolateral oral subnucleus displayed more caudal labelling than animals that were injected into the dorsomedial oral subnucleus. These findings show the existence of anatomical connections from the caudal part to the oral part of the spinal trigeminal nucleus in the rat. The connections conserve the somatotopic distribution of primary afferents in the two subnuclei. They provide an anatomical substrate for the indirect activation of trigeminal oral subnucleus neurones by somatosensory stimuli through the caudal subnucleus.

Calbindin-D28k mRNA expression in magnocellular hypothalamic neurons of female rats during parturition, lactation and following dehydration.

Recent studies indicate that calcium binding proteins may play a role in determining the electrical firing patterns of the hypothalamic magnocellular oxytocin (OT) and vasopressin (VP) neurons. In this study we have examined the calbindin-D28k mRNA content of magnocellular neurons in the supraoptic (SON) and paraventricular (PVN) nuclei and determined whether changes in expression correlate with the specific patterns of electrical activity displayed by these cells under different physiological circumstances. In situ hybridization with [35S]-labelled oligonucleotides revealed a heterogeneous pattern of calbindin-D28k mRNA expression in the SON and magnocellular PVN. Quantitative analysis demonstrated that the number of silver grains/cell in the dorsal half of the SON was approximately 30% higher (P < 0.05) than that of the ventral half of the nucleus. Within the PVN, calbindin-D28k mRNA-expressing neurons were detected in the medial magnocellular division of the PVN but not in magnocellular cells forming the core of the lateral magnocellular division. Dehydration for 24 h did not alter calbindin-D28k mRNA expression in the SON, PVN or cingulate cortex. In parturient and lactating rats, calbindin-D28k mRNA levels were significantly (P < 0.05) reduced in the medial magnocellular division of the PVN compared with virgin animals. No significant differences in calbindin-D28k mRNA expression were observed in either ventral or dorsal halves of the SON, or in the cingulate cortex of these animals. These results provide evidence for the differential expression of calbindin-D28k mRNA by hypothalamic magnocellular neurons and suggest that OT cells may express more calbindin-D28k mRNA than VP neurons. The reduction in calbindin-D28k mRNA expression by putative OT neurons of the PVN at the time of parturition and lactation supports the hypothesis of Li and colleagues (J. Physiol., 488 (1995) 601-608) that calbindin may play a part in determining the electrical firing patterns of magnocellular neurons. However, the absence of any similar decrease in the SON suggests that changes in calbindin-D28k mRNA expression are not essential for OT neurons to exhibit episodic bursting behavior.

Differential expression of advanced glycosylation end-products in neurons of different species.

The developmental time course and life span of the human brain are different from those of laboratory animals. These variations may be the reflection of metabolic differences of the neurons between different species. Using immunocytochemistry, we show that pyramidal neurons accumulate advanced glycosylation end products (AGEPs) formed by the Maillard reaction. However, the patterns of AGEPs accumulation in the pyramidal neuron were quite distinct between human and the 4 different animal species (horse, calf, pig, and rat) examined. In the human pyramidal neuron, AGEPs depict a granular, perikaryonal distribution, whereas in the animal brains, AGEPs show a nuclear staining pattern. The different patterns of AGEPs distribution in the pyramidal neurons suggest that AGEPs is an in vivo biochemical marker which distinguishes human pyramidal neurons from those of animals, and may help characterise pathologies specific to human.

Nociceptive stimulation activates locus coeruleus neurones projecting to the somatosensory thalamus in the rat.

In the thalamus, noradrenergic output from the pontine nucleus locus coeruleus (LC) may actively shape the response properties of various sensory networks en route to the cortex. Little is known, however, about the involvement of ascending noradrenergic innervation of the somatosensory thalamus in the processing of nociceptive information. To address this question, we combined the study of Fos expression upon nociceptive tooth pulp stimulation in the anaesthetized rat, with the detection of retrogradely traced neurones from the somatosensory thalamus. Cell bodies labelled retrogradely from the left thalamus were observed on both sides of the LC, with an ipsilateral predominance (n = 8). Electrical stimulation of the right incisor pulp (n = 4) provoked a significantly stronger Fos expression (around twice) than sham surgery (n = 4), in both the ipsi- and contralateral LC. Significantly larger numbers of double labelled neurones were counted in the LC of tooth-pulp-stimulated animals (representing around 30% of retrogradely labelled cells in LC) than in the LC of sham animals. They were found bilaterally, but with a clear, significant, ipsilateral (i.e. left) predominance. The present data offer an anatomical framework to understand how the LC is involved in the sensory processing of nociceptive information in the thalamus. For the first time, it is shown that nociceptive stimulation activates LC neurones projecting to the somatosensory thalamus. This suggests a new role for LC in modulating nociception within the thalamus.

Towards a pain treatment based on the identification of the pain-generating mechanisms?

Despite continuous improvements in available pain treatments, many patients with chronic pain still remain insufficiently relieved. Although such therapeutic failures are often ascribed to pharmacological or psychological factors, difficulties in elucidating pain-generating mechanisms may be the main cause of insufficient pain management. These difficulties arise from several origins, including the unsuitability of the usual classification of pain, the exclusive use of etiology or symptom criteria as the main dimension of pain to guide the choice of therapeutic agents, the inadequate interpretation of sensory deficit, the lack of identification of the injured tissues, the absence of objective pain assessment by psychophysical methods. In this paper, we review briefly some fundamental knowledge to determine pain treatment based on the identification of the physiopathological mechanisms of pain. We advocate that once pain-generating mechanisms are known, it becomes possible to establish the appropriate treatment of pain.

Central inhibitory effects of muscimol and bicuculline on the milk ejection reflex in the anaesthetized rat.

1. In order to determine whether GABAergic mechanisms are involved in the control of the milk ejection reflex in the rat, we examined the effects of central administration of a GABAA receptor agonist (muscimol) and antagonist (bicuculline) on the milk ejection reflex in the urethane-anaesthetized rat. 2. Intracerebroventricular (i.c.v.) injection of both muscimol (n = 17), at doses of 5, 10 and 20 ng, and bicuculline (n = 15), at doses of 0.01, 0.1 and 0.3 microgram, inhibited the milk ejection reflex in a dose-dependent manner. The bicuculline-induced inhibition was accompanied by desynchronization of the electroencephalogram and, at the highest dose, by alteration in the sensitivity of the mammary gland to oxytocin. No significant effect on the milk ejection reflex was seen with i.c.v. isotonic saline (n = 5). 3. Injection of 20 (n = 5) or 40 ng (n = 2) muscimol or 0.1 microgram bicuculline (n = 5) i.c.v. did not significantly alter the rise in intramammary pressure evoked by electrical stimulation of the neurohypophysis. 4. Bilateral 400 nl microinfusions directly into the supraoptic nuclei of either muscimol (20-100 ng microliter(-1); n = 10) or bicuculline (0.15 micrograms microliter(-1); n = 5) [corrected] resulted in an inhibition of the milk ejection reflex, which was not accompanied by desynchronization of the electroencephalogram. 5. The effects of i.c.v. injections of muscimol (15 and 20 ng) and bicuculline (0.01, 0.12 and 0.3 microgram) on the electrical activity of twenty-seven antidromically identified supraoptic magnocellular neurones were examined. Both compounds resulted in an inhibition of the background firing of oxytocinergic and vasopressinergic cells, and delayed the occurrence of high frequency bursts in oxytocin neurones. In five supraoptic neurones, bicuculline induced a transient activation before inhibition. 6. The powerful inhibitory action on the milk ejection reflex of both muscimol and bicuculline provides evidence for the importance of GABA neurones in maintaining the functional integrity of the mechanisms which allow the intermittent and pulsatile release of oxytocin during suckling.

Density of transient K+ current influences excitability in acutely isolated vasopressin and oxytocin neurones of rat hypothalamus.

1. The transient outward K+ current (ITO) was studied using whole-cell recording in immunocytochemically identified oxytocin (OT; n = 23) and vasopressin (VP; n = 67) magnocellular neurosecretory cells (MNCs) acutely isolated from the supraoptic nucleus of adult rats. 2. The peak density of ITO during steps to -10 mV was 26 % smaller in OT-MNCs (355 +/- 23 pA pF-1; mean +/- s.e. m.; n = 18) than in VP-MNCs (478 +/- 17 pA pF-1; n = 52). No differences were observed in the voltage dependence of activation or inactivation. 3. Kinetic analysis revealed two components of ITO inactivation in both OT-MNCs (tau1 = 9.2 +/- 0.4 ms and tau2 = 41.2 +/- 1.6 ms; n = 18) and VP-MNCs (tau1 = 12.4 +/- 0.4 ms and tau2 = 37.1 +/- 1.2 ms; n = 52). Although the density of the rapid component (tau1) was not different (275 +/- 13 versus 265 +/- 16 pA pF-1, respectively), the slow component (tau2) was markedly smaller in OT-MNCs (183 +/- 19 versus 331 +/- 16 pA pF-1 in VP-MNCs). 4. In unidentified MNCs, 0.5 mM 4-aminopyridine reduced ITO amplitude by 29% and decreased the latency to spike discharge by about 70% during depolarization from -70 mV. Latency to discharge from potentials less negative than -60 mV, where ITO is inactivated, was unaffected. 5. Comparison of latency to spike discharge in identified cells showed that OT-MNCs achieve spike threshold twice as fast as VP-MNCs when depolarized from -70 mV. The lower density of ITO in OT-MNCs, therefore, accelerates the rate at which excitation can occur in response to depolarizing stimuli and may facilitate the occurrence of higher frequency discharges in OT-MNCs during physiological activation.

[Compensatory alveolar inclinations in sagittal dysharmonies of the skeletal base]. / Inclinaisons alvéolaires compensatrices des dysharmonies sagittales des bases squelettiques.

544 cases analysis have shown that the sagittal maxillo-mandibular discrepancies happens to be a very frequent problem in orthodontics. They are often compensated by dento-alveolar inclinations, when no muscular disorder, functional or constitutional, exists. The basal discrepancies modify the direction of dental inclinations. It is the normal action of the musculature which determines the correctional inclination that must be respected. We have to use light therapeutic methods and respect these natural dental movements.

[The abandonment of treatment in orthodontics]. / Etude des abandons de traitement en orthopédie dento-maxillo-faciale.

Orthodontic treatments are frequently given up: a recent study of the C.N.A.M.* has shown a rate of 51%. In spite of lightest and least constraining therapeutic methods, the authors estimate that 27% of the patients stop their treatment before the end. --Looking for the reasons why, they have found a "central nucleus" of about 27% which builds up a constancy of abandoned treatment undeniably in relation with an ethical phenomenon, plainly concerning the individual or the family. --That is to show the advantage of our adapted therapeutic possibilities to answer the patients' requests, and to clearly explain their benefits and their possible difficulties. In other words we have to admit the necessity of a more medical than mechanical approach in orthodontics.

Effects of central GABAB receptor modulation upon the milk ejection reflex in the rat.

In order to investigate the role of central GABAB receptors in the control of the milk ejection reflex, we have examined the effects of third ventricular and bilateral supraoptic nucleus (SON) injections of a GABAB receptor agonist (baclofen) and antagonist (hydroxy-saclofen) on the milk ejection reflex in the urethane-anaesthetised rat. In addition, microdialysis studies have evaluated whether the activation of GABAB receptors in the SON is able to modulate the release of GABA and glutamate, two major neurotransmitters involved in the regulation of the milk ejection reflex. Intracerebroventricular injections of baclofen (n = 9) in doses of 10, 50 and 100 pmol inhibited the milk ejection reflex in a dose-dependent manner, without affecting the electroencephalogram or attenuating the intramammary pressure response to intravenous injection of 0.5 mU exogenous oxytocin. Hydroxy-saclofen given into the third ventricle in doses of 100 pmol (n = 2) and 500 pmol (n = 4) did not modify the pattern of the milk ejection reflex. Bilateral SON microinfusions of baclofen in doses of 80 (n = 2) and 200 pmol (n = 4) did not modify the pattern of the milk ejection reflex. In microdialysis experiments (n = 8), inclusion of baclofen into the microdialysate at a concentration of 500 microM had no effect upon basal or potassium-stimulated GABA and glutamate outflow. These results show that the activation of GABAB receptors located outside, but not within, the SON are capable of inhibiting the milk ejection reflex. In contrast to our previous findings regarding the GABAA receptor, we found no evidence for a tonic role of GABAB receptors within the neural network inducing the periodic synchronous bursting of oxytocin neurons during suckling.